The autumn winds may blow chilly and cold, but they’ve carried with them a month of fascinating developments from the wide world of cancer research.

As you cozy up by the fire and pour a hot beverage, why not take in the second edition of Unboxing Cancer News? We have a piping-hot kettleful of stories this month, including insight into why some never-smokers may develop lung cancer; the effects of early-life sugar exposure on cancer risk; a strategy for chemotherapy pain prevention derived from psilocybin mushrooms, of all things; and more.

Magic Mushroom Trips Chemotherapy’s Pain Circuit

What a long, strange history psilocybin’s had—from disrupting the breakfasts of unsuspecting English families to undergoing clinical trials for post-traumatic stress disorder (PTSD) and smoking cessation. But a new study from Science shows yet another possible application for the freaky fungi: relieving pain from some cancer treatments.

Chemotherapy regimens that use platinum or taxanes to treat cancer frequently cause a condition known as chemotherapy-induced peripheral neuropathy (CIPN), a cluster of nerve-damage symptoms that includes numbness, sensory impairment, unpleasantly heightened sensitivity to temperature, and straightforward pain. The toll that CIPN takes on some patients can even lead to chemotherapy discontinuation, and though treatments exist that somewhat attenuate it, preventive measures to preempt CIPN have not hitherto existed.

Enter the Psilocybe genus: the colloquially “magic” mushrooms that contain the serotonergic hallucinogen psilocybin. But psilocybin is not just an experiential enhancement for Burning Man—it is also a potent activator of serotonin 2A.

Serotonin 2A receptors, the authors of the Science study reasoned, could bind to psilocybin and activate their known pro-plasticity and mitochondria-regulating effects—mechanisms that could, in turn, confer protective effects on the nerves normally damaged by chemotherapy.

In mice, one dose of psilocybin reduced the post-chemotherapy pain, and two doses eliminated it altogether. On a molecular level, they found that the psilocybin treatment activated a signaling pathway (TrkB-Akt-PAK5) that preserves mitochondrial transport along nerve axons, which chemotherapy otherwise disrupts. Because the mitochondrial transport remained intact, chemotherapy did not lead to a deprivation of energy in the cells’ axonal regions, thus preventing damage to the nerves and, ultimately, pain.

Although the study was limited to mice, it wouldn’t be the first time that psilocybin was used in a cancer setting; an ongoing clinical trial is testing whether the hallucinogen can help treat depression and anxiety in patients with advanced cancer.

Ultimately, however, psilocybin was merely a means to an end for discovering the pain prevention mechanism. The researchers found that a comparable, nonhallucinatory agonist of serotonin 2A, tabernanthalog, was just as effective in preventing CIPN in chemotherapy-treated mice, and they concluded that these prophylactic effects against CIPN warranted further clinical investigation.

Ensuring Cancer Won’t Get the Last Word: Saving the Voice Box

For patients with locally advanced head and neck squamous cell carcinoma (HNSCC), treatment can be extensive and have negative effects on quality of life.

One option includes radical surgery—an extensive surgery to remove the tumor and all surrounding tissue—but this procedure often results in organ dysfunction, such as difficulties with speaking and eating, as well as facial disfigurement. This approach is also associated with high rates of recurrence and metastasis.

Fortunately, advances in immunotherapy regimens for locally advanced HNSCC has led to greater tumor shrinkage and improved overall survival when immunochemotherapy (ICT)—which combines chemotherapy with immunotherapy—was given before surgery. Given these positive results, a new study in Clinical Cancer Research asked if this strategy could allow for less extensive surgery to help maintain positive functional outcomes.

To test this, researchers conducted a clinical trial that treated 52 patients with locally advanced resectable HNSCC with three cycles of ICT. Tumor response was monitored by imaging during ICT treatment. Patients who had greater than or equal to 50% tumor regression were eligible to undergo less extensive, reduced-volume surgery to remove residual tumor while minimally affecting nearby structures and organs; and those who had less than 50% tumor regression received standard-volume surgery.

At two years, 90% of patients who received reduced-volume surgical treatment were still alive and had not experienced disease recurrence or metastasis. Notably, this approach maintained laryngeal function in 100% of patients with laryngeal or hypopharyngeal cancers, supporting a primary goal of organ preservation.

In contrast, patients who underwent standard-volume surgery had a two-year disease-free survival rate of only 20%. One of three patients who had laryngeal or hypopharyngeal surgery experienced complete loss of laryngeal function.

The study further revealed that the higher levels of PD-L1, a protein that helps cancer cells evade the immune system, was positively correlated with response rate to ICT, indicating that PD-L1 expression may serve as a biomarker for predicting response to ICT.

Together, the results of the study provide a strong rationale to further investigate whether surgery may be individually tailored based on tumor response to ICT.

Not-so-sweet Connection Between Sugar and Cancer

Sorry for those with a sweet tooth, but there is no sugarcoating the results from our next study published in the Proceedings of the National Academy of Sciences: Less sugar in early childhood may mean a lower risk of cancer later in life. But before we get into the granular details of the study, we first need to unwrap a bit of history. During World War II, the United Kingdom started to ration individual sugar intake to about 40 grams per day for adults and 15 grams for children. When this policy was lifted in 1953, average sugar intake nearly doubled.

This sudden change from sugar rationing to sugar rush has allowed researchers to examine the potential long-term effects of sweet treats on a variety of health conditions, with this latest study focused on cancer. The researchers analyzed data from 64,761 UK Biobank participants born between 1951 and 1956 to ensure they captured information for individuals born well within the rationing period until a few years after. Specifically, they looked at the period from conception to a person’s second birthday since this is a critical period of the body’s development.

They found that people who experienced longer durations of sugar rationing during that period of development had lower incidence rates of five cancer types: liver/intrahepatic bile duct (69%), prostate (52%), lung (41%), rectal (40%), and breast (36%). The researchers noted this was a dose-dependent relationship and that these changes only started to appear decades later following sugar rationing’s bitter end.

The researchers also uncovered that while sugar highs may be fleeting, the behavioral and biological effects may be everlasting (so Willy Wonka may have been onto something). People who experienced sugar rationing in their early life continued to consume less sugar five decades later. Further, these individuals also had healthier, more diverse diets and consumed less food overall. Less sugar in early life may also help people age slower—biologically speaking. While chronological age measures how long one has been alive, biological age measures the condition of one’s cells, tissues, and organs. Those exposed to longer periods of sugar rationing were found to be biologically aging about 2.2 years slower.

For a bit of sweet relief, the researchers say this doesn’t necessarily mean children should never eat sugar, but to at least keep in mind sugar’s potential impact on the body during early childhood development.

Trekking the Appalachian Trail to the Origin of Never-smokers’ Lung Cancer

Smoking is the leading risk factor for lung cancer, but not everyone who develops the disease has a history of smoking. An estimated 15% to 20% of lung cancer patients have never smoked. Understanding why lung cancer develops in never-smokers remains an important area of research.

One potential clue emerged about 20 years ago when researchers reported a family in which several members had non-small cell lung cancer and carried an inherited mutation in epidermal growth factor receptor, or EGFR, known as T790M. EGFR is a protein involved in signaling pathways that regulate cell growth. T790M is particularly well known because it can arise in lung tumors during treatment and drive resistance to EGFR-targeted drugs. Mutations in the EGFR gene are important targets for several lung cancer therapies.

The finding provided early evidence that a mutation well known for its role in lung cancer treatment resistance could also be associated with inherited susceptibility to the disease, but it was so rare that further conclusions were limited.

Now, a new study published in Science has examined the connection on a much larger scale. The team analyzed genetic and health data from more than 3.3 million people using direct-to-consumer genetic testing data from 23andMe to investigate inheritable genetic risk factors of cancer.

The researchers focused on people who carry T790M in their germline, meaning the mutation is inherited at birth. They compared people with lung cancer to those without the disease and asked if EGFR T790M was more common among those who developed lung cancer.

Carriers of the variant had a 25-fold increased risk of lung cancer. People who never smoked and had the mutation were more than 60 times more likely to develop lung cancer than noncarriers. Notably, EGFR T790M was not associated with an increased risk of cancer in any other organ.

For those interested in history, the authors found that the mutation was more common in certain parts of the Southeastern United States and were able to trace the ancestral lineage to British and Irish groups that settled in Southern Appalachia about 200 to 225 years ago.

While the researchers are not yet sure how this mutation increases the risk of lung cancer or why it is tissue specific, the findings could have important implications for identifying people who may benefit from early detection and treatment strategies.

Who binge drinks more often: young men or women? Twenty-five years ago, the answer was unquestionably young men—with rates twice as high as young women. But today, rates among young women have caught up to and even slightly surpassed those of young men.

This shift has led researchers to ask whether binge drinking could be one of many factors contributing to the rise of early-onset breast cancer.

Alcohol consumption at any level is known to increase the risk of certain cancers, including breast, colorectal, liver, stomach, esophageal, and some types of head and neck cancers, according to the AACR Cancer Progress Report 2026. In fact, even one drink per day raises the risk of breast cancer. However, various studies have established a dose-response relationship between alcohol and cancer, meaning higher levels of alcohol consumption can lead to a higher risk of these cancers.

“Biologically, it makes sense why heavy, fast consumption of alcohol could be more damaging than slower, more chronic exposure,” said Mary Beth Terry, PhD, a professor of epidemiology and environmental sciences at Columbia University, who has been studying the relationship between alcohol and breast cancer risk, and presented a talk on this subject at the San Antonio Breast Cancer Symposium (SABCS) 2025. In an interview with Cancer Research Catalyst, Terry pointed to animal studies that have demonstrated the physiological impact of binge drinking.

When you drink alcohol, Terry explained, your body first converts ethanol into a harmful toxin called acetaldehyde, and then quickly converts acetaldehyde into a harmless substance called acetate. However, the more alcohol you drink, the harder it is for the body to process acetaldehyde fast enough. A build-up of this toxin can then cause DNA damage, which is one of the ways that alcohol consumption can lead to cancer. 

In addition to that biological rationale, Terry said the rise of binge drinking in young women has corresponded with a concerning trend in cancer incidence.

“We have seen an increase in the number of women under 40 getting breast cancer at the same time binge drinking in young women has gone up,” Terry explained, “so we wanted to take a closer look to see if there could be a connection.”

Can Binge Drinking Lead to Breast Cancer in Young Adults?

To better understand whether binge drinking could play a unique role in breast cancer, Terry and colleagues examined national breast cancer incidence data collected between 2010 and 2019 and paired it with drinking-pattern data from 2000 to 2019.

Past studies have identified a greater association between breast cancer risk and binge drinking compared with moderate alcohol use, specifically in cases of premenopausal breast cancer, which is generally diagnosed in women under 50. To further understand the association, her team examined four subtypes of breast cancer (luminal A, luminal B, ERBB2-enriched, or triple-negative) in 20- to 39-year-old women with population-based data on the following alcohol consumption categories: binge drinking, daily drinking of one or more drinks per day, and daily drinking of two or more drinks per day.

They evaluated the data in two models: a 10-year lag model that examined alcohol exposure a decade prior to cancer diagnosis to account for the time it takes for cancer to develop and a cumulative model that combined the sum of alcohol consumed over the 10 years leading up to diagnosis.

“We were interested in examining whether alcohol exposure affected cancer risk only after a certain time had passed or whether the total amount of alcohol was more important,” Terry explained. “Generally, when exposures like alcohol can affect tumor initiation and growth you would expect the cumulative exposures to matter more.”

In both models, however, greater rates of binge drinking were associated with higher rates of luminal A breast cancer (5% greater in the 10-year-lag model and 6% in the cumulative model). Binge drinking prevalence was not associated with a higher rate of ERBB2-enriched or triple-negative breast cancers, and only the cumulative model found it was associated with the rate of luminal B breast cancers.

This, Terry explained, is consistent with what we know about the role of alcohol and the development of hormone receptor (HR)-positive breast cancers, as alcohol can alter hormone levels. While both luminal A and luminal B are HR-positive cancers, the luminal B subtype typically has lower levels of HR expression. ERBB2-enriched cancers can be HR-positive or HR-negative, but can also have lower HR expression, while triple-negative cancers are HR-negative.

“While a 5% to 6% increase in cancer risk may seem modest, even a small percent increase for a common cancer like breast cancer can still have public health importance,” Terry said. “From a public health perspective, we know that it may be difficult to get people to stop drinking entirely—which would be ideal given any amount has been shown to be causal for breast cancer—but we can at least explain the dangers of binge drinking and explain why it is important to cut back.”

Even if that advice may sound obvious, Terry emphasized that most individuals are not receiving it. A study from the U.S. Centers for Disease Control and Prevention (CDC) found that only about 38% of adults were asked by their doctor if they binge drink, and if they reported doing so, 80% were not advised to reduce their drinking.

Concerning Trends in Binge Drinking

A CDC study from 2020 reported that the total number of drinks consumed annually during binge-drinking sessions increased significantly, between 2011 and 2017, from 472 to 529, with the largest increases among those 35 to 44 years old (26.7%), individuals with less than a high school diploma (45.8%), and those with household incomes under $25,000 (23.9%).

In 2024, an estimated 57 million adults 18 or older reported binge drinking, according to the AACR Cancer Disparities Progress Report 2026, which highlighted how patterns vary considerably across races, ethnicities, and demographics. For example, some studies suggest that experiences associated with structural racism may contribute to higher rates of binge drinking among affected populations. The report also highlighted higher rates of binge drinking among veterans who served in combat zones (24.8%) compared with those who did not (19.4%).

More recently, binge drinking across all ages groups is on the decline—dropping from 21.7% to 19.5% between 2021 and 2025, according to the 2025 National Survey on Drug Use and Health from the Substance Abuse and Mental Health Services Administration. However, 18- to 25-year-olds reported the highest percentage of binge drinking at 26.7%, which represents 9.6 million young adults. And while those under the legal drinking age (12 to 20) reported drinking less (a drop from 15.6% to 13.7%), their rates of binge drinking have remained stable since 2021.

Is Binge Drinking Linked to Early-onset Colorectal and Gastrointestinal Cancers?

To this point, the long-term impact of binge drinking on early-onset cancers has been most documented in breast cancer, but that is only one of several types of cancer becoming more commonly diagnosed in individuals under 50. And Yin Cao, ScD, MPH, a professor of surgery and molecular epidemiologist at Washington University School of Medicine in St. Louis, said there are reasons to suspect binge drinking could contribute to other early-onset cancers, such as colorectal and gastrointestinal cancers.

“Limited human evidence suggests that binge drinking may promote the passage of gut-derived bacterial products into circulation, while experimental studies in mice indicate that chronic binge drinking can exacerbate intestinal inflammation and increase susceptibility to intestinal infection,” explained Cao, who co-leads the Cancer Grand Challenges Team PROSPECT investigating the global rise of early-onset colorectal cancer. Researchers are examining how impaired intestinal barrier integrity and chronic inflammation could contribute to early-onset colorectal cancer.

Samantha Rees, PhD, MPH, a postdoctoral fellow at the BC Cancer Research Institute in Canada, has been focused on better understanding modifiable risk factors related to colorectal and breast cancers. At last year’s AACR Special Conference in Cancer Research: The Rise in Early-onset Cancers—Knowledge Gaps and Research Opportunities, she presented a study that examined the differing risk factors between early-onset colorectal cancers and late-onset colorectal cancers.

In results that have since been published, Rees and her colleagues found that those with early-onset colorectal cancer were 3.22 times more likely to engage in binge drinking during their peak alcohol consumption years vs. those with late-onset colorectal cancers.

“We were able to identify important hypotheses regarding the role of alcohol consumption in early-onset colorectal cancer development, but ultimately these associations are worth exploring using more rigorous study designs,” Rees said. “But, in general, educating the public about known risk factors for cancers is important and alcohol consumption, extending to binge drinking, is a known carcinogen and a behavior that can be modified.”

Beyond binge drinking, Cao’s team is interested in examining the impact of other modern drinking habits, such as consuming alcohol without meals.

“Increasingly, more young adults deliberately skip meals before drinking to offset the calories in alcohol, become drunk faster, or save money for alcohol,” Cao explained.

In a cohort study of 347,591 current drinkers in the UK Biobank, Cao and her colleagues discovered that after adjusting for total alcohol intake, drinking without meals resulted in a 10% higher risk of gastrointestinal cancers (gastric, liver, and rectal) compared with those who drank with meals. Additionally, drinking without meals had a stronger association with earlier-onset gastrointestinal cancers.

“My message to the scientific community is we need to do a better job of capturing data and elucidating the impact of emerging drinking habits,” Cao said. “Otherwise, we will lose the opportunity to settle how these habits could be contributing to cancer’s development.”

Cao also echoed Rees’ message about educating the public regarding the need to reduce total alcohol consumption. “Even though it’s one of our prime social behaviors, it is important from a cancer prevention perspective,” she said.

A lot has happened in Carolyn Searles’ life over the past year. She celebrated her 36th birthday last September by trying out for “Wheel of Fortune.” She wasn’t selected and joked that she was “devastated,” as anyone would be who missed out on the chance to appear on one of their favorite gameshows. But she had a beautiful 2-year-old daughter, was 16 weeks pregnant with her second child, and took a weekend trip away with her husband, Andrew, for her birthday, which washed away any lingering disappointment.

That is, until her fortune took a spin she didn’t expect.

When they returned home, Carolyn discovered a golf ball-sized lump in her armpit. The threat of cancer was something Carolyn has lived with since she was 29 years old and tested positive for the BRCA1 mutation, which significantly increases the risk of developing breast, ovarian, and other cancers. That threat—and watching her close friend die of inflammatory breast cancer—led Carolyn to get a prophylactic double mastectomy at 31. Her doctors informed her this surgery would reduce her chances of getting breast cancer to around 1% to 5%.

But here she was with a lump near her breast and awaiting the results of a biopsy. The MyChart notification came through, she scrolled down, and saw the word “malignant.” Her world stopped. Only a few moments earlier, her OB/GYN had handed her a sonogram of a beautiful baby boy. But now, with a stage 2B triple-negative breast cancer diagnosis, she did not know what would happen to her or her baby.

Over the course of the next year, she would learn how it’s possible to undergo some cancer treatments while pregnant. She would give birth to a healthy baby boy, Blake. She would be told her treatment resulted in no signs of cancer. And she would decide that others should know all of this is possible.

“I had no idea until it happened to me that you can receive chemotherapy when you’re pregnant,” Carolyn said. “People need to know that there’s a chance for survival for you and your baby. Even if I reach one person who’s in the same situation, then I feel like I’ve made a difference.”

Carolyn is one of seven survivors who shared their stories for the 2026 edition of the Cancer Progress Report, which is published annually by the American Association for Cancer Research (AACR). This year’s report was unveiled during a congressional briefing on Capitol Hill on September 16, just short of a year from Carolyn’s diagnosis. She was in attendance with her husband, and the next day, they were joined by her two sisters and mother-in-law as they returned to the Capitol—along with more than 300 others—for the Rally For Medical Research. Together, they wanted to make sure their congressional representatives heard Carolyn’s story—and what medical research meant to their whole family.

Three Sisters With a BRCA1 Mutation

It’s impossible to tell Carolyn’s story without telling her family’s story. Not only because they have been with her every step of the way, but because both of her sisters also have a BRCA1 mutation.

The eldest of the three, Emily Smith, always had a feeling something in their family was leading to a higher risk of cancer. Their aunt is a three-time triple-negative breast cancer survivor (still living “her best life,” per the sisters), and their father is a prostate cancer survivor. So, when Emily’s work offered direct-to-consumer genetic testing, she took them up on it. Tests like this for the BRCA1 mutation were not available when their aunt was first diagnosed with cancer, Emily said.

“It was thanks to research led by Mary-Claire King—which was funded in part by the National Institutes of Health (NIH)—that the BRCA1 gene was discovered,” Emily explained. “It is tremendous to think about the progress that has been made in screening and treatment for triple-negative breast cancer since our aunt was first diagnosed in her early 30s.”

Emily, who is a nurse practitioner in radiation oncology at Penn Medicine, where Carolyn was treated, says the treatment regimen that Carolyn received is another example of that progress. Based on the phase III clinical trial KEYNOTE-522, the U.S. Food and Drug Administration (FDA) approved the immunotherapy pembrolizumab (Keytruda) in combination with chemotherapy in July 2011 for early-stage triple-negative breast cancer. Under this regimen, pembrolizumab is given with carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide before surgery and then as a monotherapy after surgery. Carolyn, however, received an adapted version of this regimen in which both surgery and pembrolizumab were delayed until after she gave birth to avoid harming the baby.

“The fatigue was next level, and I was not sure if it was because I was pregnant or if it was from the chemo,” Carolyn said. “But the way to battle fatigue is basically to keep on moving and so that’s what I did.”

Carolyn continued to work full-time throughout her pregnancy and treatment, while also taking care of daughter (now 3)—with a lot of help from family and friends. After giving birth, she had a completion mastectomy to remove residual breast cancer tissue—which Emily explained can remain after risk-reducing mastectomies and even increase during pregnancy—and finished her chemotherapy. Tests showed she had a pathological complete response, which indicates no signs of cancer.

Even before Carolyn’s cancer diagnosis, each one of the sisters has been willing to contribute to continued progress in cancer screening, prevention, and treatment. Emily has participated in clinical trials evaluating preventive methods for both breast and ovarian cancers. Meanwhile, Carolyn and her younger sister, Julia Straube, are participating in biobank studies where they are donating their breast tissue and blood samples for future research.

“I want to opt into anything that will further research,” Julia said. “Because it is not just about our future and our longevity. I like to think about there being better options for my kids and other patients in the future with this mutation.”

Measuring the Impact of Progress

One of the goals of the annual AACR Cancer Progress Report is to illustrate how much progress is being made—and how research fuels that progress. Between 1991 and 2024, the overall cancer mortality rate declined by 35%, resulting in more than 4.8 million cancer deaths averted. During the congressional briefing for the report, AACR CEO Margaret Foti, PhD, MD (hc), said the true measure of progress is in those lives saved.

“Behind every discovery are patients, their families, their loved ones, who want to spend more time with each other,” Foti said. “Cancer touches every family, and my family has not been immune to that. My sister and brother both had cancer and they’re in great shape today because of research and I am very, very grateful.”

Carolyn and her sisters said that between discovering they all have a BRCA1 gene mutation and Carolyn’s cancer diagnosis, this is the most time they have spent together since they were kids living in their parents’ house.

“No one wants to bond over any of this, but we trust each other, we support each other, and it really has brought us so much closer together,” Carolyn said.

A similar sentiment was shared by each of the congressional representatives who made an appearance during the briefing.

Senator Shelley Moore Capito (R-WV) said her brother was diagnosed with cancer last year, and he is now in full remission. “I’m certain if this had happened 20-30 years ago … he’d still be struggling, but he has had great care. So, thank you to all of the researchers and others who have brought about not just the hope of treating [cancer] but cures.”

Representative James R. Walkinshaw (D-VA) is carrying on the legacy of his “predecessor, mentor, and best friend” Gerry Connolly who passed away from esophageal cancer. While getting treatment, Connolly wrote a bill that required the government to study esophageal cancer among federal employees and retirees to help identify opportunities for early detection. Later renamed the “Gerald E. Connolly Esophageal Cancer Awareness Act” in his honor, Walkinshaw said he had the great privilege of getting the bill across the finish line.

Although Ben Sasse, former Senator of Nebraska, could not be there in person, he sent a prerecorded video sharing how he was recovering from surgery. Normally, he said, surgery is not associated with positive news, but in this case, it is a testament to how far cancer treatment has come. In December, Sasse was diagnosed with pancreatic cancer and given three months to live. His doctors said he was post-surgical or, in Sasse’s words, “too toasted” for surgery. But he joined a clinical trial for the now FDA-approved daraxonrasib (Rasonque) and is still alive nine months later.

“We measure progress with data, exact measurements, refined hypotheses, careful tests, oceans of spreadsheets. But why do we do it?” Sasse said in his video. “We do it because my family and I got to have dinner together a couple days ago and many other families get to do that—to measure the progress of time with particular hugs, particular breakings of bread, more conversation, more life, more gratitude.”

Daraxonrasib is also an example of how “we are in a remarkable era of scientific discovery like never before,” AACR President Keith T. Flaherty, MD, FAACR, said during the briefing. In fact, he explained that it wasn’t long ago that KRAS mutations—which daraxonrasib targets—were considered undruggable, and now we have a new treatment for one of the deadliest cancers.

Cutting-edge innovations like this are why Capito, who currently serves as the chairperson on the Labor, Health and Human Services, Education, and Related Agencies Appropriations Committee, assured those in attendance that the Senate remains “deeply committed to NIH research funding.”

Continuing to Fuel American Medical Innovation

Senator Sasse, daraxonrasib’s approval, and the impact of cancer on families were also popular topics of discussion among many others at the Capitol. At a participants’ reception held the night before the Rally For Medical Research, Reed Jobs, whose father died from pancreatic cancer, pondered about the promise of this breakthrough with daraxonrasib and what other innovations could be around the corner.

“This is giving hope to millions of families all over the world,” Jobs said, who founded the venture capital firm Yosemite to fund cancer research. “American innovation has an incredible, proud, and ongoing history. This is where cancer is going to be made nonlethal. I truly believe that. And I think that that’s going to happen in the course of most of our lifetimes.”

NIH Director Jay Bhattacharya, MD, PhD, reminded people at the reception that while daraxonrasib’s approval only recently made splashy news, the research behind it started decades ago with the discovery of the KRAS gene through NIH research. Recently, Bhattacharya said he has gained an even greater appreciation for such basic science discoveries after his mom passed away from congestive heart failure earlier this year. He explained his mother would have died at a much younger age if she had been diagnosed 20 years ago, before research led to new treatments for this disease.

“The real advances that have given hope to families everywhere, it’s so easy to take them for granted, but we must never do that,” Bhattacharya said. “They result because of sustained work by people who devote their lives to it. And at the NIH, we are absolutely committed to making sure that we train the next generation of scientists, make sure their ideas are supported, that we focus on things that unite all of us.”

Like Capito, Senator Dick Durbin (D-IL) ensured Rally participants that members of Congress would reject any administration effort to cut the budget for NIH on a bipartisan basis.

Rally Participants Tell Their Representatives What Science Makes Possible

Since 2013, hundreds of people have attended the Rally for Medical Research Hill Day each year to advocate for robust and sustained funding for NIH. While AACR serves as the founding organizer and lead sponsor, more than 400 organizations across every area of medical research unite to spread this message. This year, one of the key messages was an ask to increase the NIH base budget in fiscal year 2027 of at least $51.3 billion.

To deliver this message, Carolyn’s family joined a group of about 20 other Pennsylvania constituents, which included AACR President-Elect and Director of Penn Medicine’s Abramson Cancer Center Robert H. Vonderheide, MD, DPhil, FAACR, and Bloomberg Distinguished Professor of Cancer Biology at Johns Hopkins Bloomberg School of Public Health Ashani T. Weeraratna, PhD, who is a member of the AACR Board of Directors.

Over the course of the day, they met with various representatives across both parties, which included but was not limited to Senator Dave McCormick (R-PA), Representative Brian Fitzpatrick (R-PA), and staff members for Senator John Fetterman (D-PA) and Representative Mary Gay Scanlon (D-PA). Each of them expressed their continued support for NIH funding.

During the meetings, the Rally participants were also able to voice their concerns to the representatives.

Weeraratna said that her institution used to accept between 10 and 15 PhD students each year in her department, but in the last two years, they have only accepted three because of the delays in funding. Further, she said the United States is starting to experience a “brain drain” of talent to other countries.

“Young researchers always used to ask me about coming to the United States to continue their studies, but recently that has not been the case,” she said. “In order to ensure we continue to deliver the best care to patients in the U.S., we need to also ensure we are continuing to nurture a pipeline of early-career researchers.”

During one of the meetings, Vonderheide emphasized how big an impact NIH funding continues to have on cancer research.

“We want to cure cancer,” he said. “Not just make it a little better—cure it. We think science can make that possible—with support.”

Science is what made it possible for Carolyn to celebrate her 37th birthday the day following the Rally; to hold her healthy baby boy, who continues to show no effects from the cancer treatment his mother received; to get to go on hayrides with her children later this fall and train rides around Christmas time; to get to celebrate Blake’s first birthday; to spend more time with her sisters; and to continue to advocate for medical research.

To get to live her life—the true measure of progress.

War imagery and terminology can sometimes be used as a metaphor for the treatment of cancer, but for some doctors and patients, the relationship between war and cancer is more than a metaphor—it is their reality. That is the case for Iryna Dudchenko, MD, PhD, who is an associate professor at Sumy State University and a practicing hematologist in the Ukrainian city of Sumy, which is on the frontlines of the conflict with Russia.

“We work amid constant air-raid alerts and logistical challenges, and sometimes treatment has to be postponed,” Dudchenko explained.

In her clinical practice, she is also increasingly seeing patients whose hematologic malignancies are now being diagnosed at later stages. To better understand why, Dudchenko is studying how the war is impacting the diagnosis of multiple myeloma while trying to identify tools that could help primary care physicians recognize possible multiple myeloma earlier and refer patients for appropriate diagnostic testing.

Dudchenko believes that international collaboration can help make this kind of research more actionable. So, along with around 100 other clinicians and researchers from Ukraine and Poland, she attended the AACR on Campus Poland/Ukraine event in Warsaw from August 6 to 7. These events are intentionally designed as smaller, highly interactive programs to support the professional growth and scientific exchange of early-career cancer researchers and clinical professionals in the region.

Organized by the American Association for Cancer Research (AACR) in partnership with the Maria Skłodowska-Curie National Research Institute of Oncology (MSCI) in Warsaw, Poland, and the Global Medical Knowledge Alliance (GMKA) Ukraine, the program focused on some of the most consequential challenges facing oncology professionals in those two countries, including detecting cancer earlier, improving patients’ quality of life, and translating research and real-world data into better clinical care.

“Despite all the challenges, we continue to work, continue to live, and want to remain in our cities,” Dudchenko said. “Programs like this give us an opportunity not only to gain new knowledge, but also to see that major international professional organizations understand the circumstances in which we work and are prepared to support change in Ukraine. That matters for physicians, for our patients, and for the development of the health care system as a whole.”

Bringing Ukrainian Research to an International Audience

Like Dudchenko, Anna Karavska, MD, is also examining the impact of the war on oncology services in Ukraine, including access to cancer care, the quality of care, and gaps within the health care system. Karavska, a surgical intern at the First Lviv Territorial Medical Union, St. Panteleimon Hospital in Ukraine, presented her research during a poster session where she spoke about the need for clinical research in her country.

“Conducting clinical trials in Ukraine is critically important,” Karavska said. “Trials give patients access to the newest and sometimes the only effective therapies, while giving Ukrainian physicians the opportunity to work according to global standards of cancer care. I hope the connections made at this conference will help build collaborations that enable more clinical trials to be conducted in Ukraine.”

As one of the two winners from the poster session—the other was Klaudia Bobak from Poland—Karavska will also get the opportunity to forge more international connections at the AACR Annual Meeting 2027, which will be held April 2-7 in Orlando.

“I am incredibly happy and sincerely grateful to AACR for this opportunity,” Karavska said. “I will do everything I can to represent Ukraine and remind our international colleagues of the importance of continuing to strengthen our collaboration to improve the quality of cancer care in Ukraine, especially during the war.”

Lessons From Ukraine Can Help the Global Oncology Community

Richard Sullivan, MD, PhD, of the Institute of Cancer Policy at King’s College London, led a session on health economics, health services research, and implementation science, and emphasized that international collaboration with Ukraine works both ways as the world has much to learn from how clinicians in the country have adapted to wartime challenges.

Sullivan said Ukrainian oncologists have demonstrated incredible resilience in their ability to get radiotherapy machines back up and working during electricity outages caused by attacks as well as to develop adaptive surgical procedures to care for patients at various stages in their diagnosis. Further, Sullivan is working with Ukrainian and Polish researchers to better understand patients’ access to high-tech medical innovations in their respective countries and how they approach the financing of cancer care, which he explained can provide useful comparisons that can drive public policy changes that improve access to care on a global scale.

“Partnership with Ukrainian colleagues is important not only as an expression of solidarity and support, but we also do a lot of work in terms of understanding the impact of conflict in Ukraine and translating that across to other European countries and other settings around the world,” Sullivan said. “This kind of two-way collaboration creates a strong foundation for long-term partnership and for further strengthening cancer care and research in Ukraine.”

Putting Patients’ Quality of Life at the Center of Cancer Care

This event also furthered the partnership between Poland and Ukraine—former adversaries who have come together following the Russian invasion of Ukraine in 2022.

“It is extremely important for us to host programs like this, collaborate with organizations such as AACR, and continue supporting Ukraine,” said Iwona Ługowska, MD, PhD, professor, head of the Centre of Excellence for Precision Oncology, and director’s representative for international affairs at the Maria Skłodowska-Curie National Research Institute of Oncology. “As a neighboring country, Poland has supported Ukraine for many years—not only by providing medical care, but also by expanding research collaboration and strengthening partnerships between hospitals. Many Ukrainian colleagues now work in our hospitals, so our countries and institutions are closely connected.”

The program was designed to address the needs of both countries, and patients’ quality of life and the growing role of patient-reported outcomes (PROs) was chosen to be one of the event’s central themes.

“We should not focus only on treatment efficacy,” said Katarzyna Pogoda, MD, a medical oncologist in the Department of Breast Cancer and Reconstructive Surgery at the Maria Skłodowska-Curie National Research Institute of Oncology, who led a session on quality of life. “Of course, we want to reduce the risk of recurrence, but at the same time, we need to think about quality of life: how to assess it, how to discuss it with patients, and how to help them stay on treatment.”

Across modern oncology, PROs are becoming an increasingly important tool for understanding the full impact of treatment. They complement traditional clinical measures by showing not only whether a therapy controls disease, but also how it affects a person’s symptoms, daily functioning, and overall well-being. Incorporating this perspective can help clinicians and researchers make treatment decisions that better reflect what matters to patients, Pogoda explained.

“We may think, ‘I’ll prescribe the medication, and the patient will take it.’ But it doesn’t work that way,” she added. “We need to talk about quality of life, how to improve it, and how to help patients manage the challenges they face so that we can achieve better treatment outcomes.”

Building Connections With an Eye on the Future

As with other AACR on Campus events, the program also featured workshops designed to equip participants with practical tools to advance their own research, including in the areas of scientific publishing, grant writing, identifying funding opportunities, and academic career development.

“This conference is especially important to us because it brought together proactive clinicians, researchers, and health care leaders who are already providing high-quality care to their patients while also being ready to take on greater responsibility—strengthening their institutions and helping drive change in cancer care in their countries,” said Inesa Huivaniuk, MD, MPA, a surgical oncologist and co-executive director of GMKA Ukraine. “It also gives us an opportunity to launch new research projects, develop our own ideas with international experts and mentors, and build partnerships that can continue well beyond this program.”

In fact, in a post-program survey, participants emphasized the practical value of the program: 97.6% said they would be able to apply what they learned directly in their work.

“For young physicians who, like me, hope to become oncologists, this is a wonderful opportunity to learn,” said Anna Trelecka, MD, an early-career physician from Warsaw conducting research in melanoma and sarcoma. “I gained a great deal of knowledge, and I think I will be able to apply it in my future research.”

Huivaniuk said the program’s potential long-term impact on early-career researchers and cancer care overall in Ukraine was central to GMKA’s decision to partner with AACR.

“For Ukrainian oncology, international collaboration opens access to joint research, mentorship, grant programs, and clinical trials, but its value goes far beyond individual professional opportunities,” Huivaniuk explained. “What matters is that Ukrainian clinicians and researchers can participate fully in the international professional community—sharing their own experience, developing research questions together, and working with partners to identify solutions that improve cancer care and patients’ quality of life. This is important for Ukraine today, and it will remain important after the war ends.”

Decades of scientific advances have transformed outcomes for many children with cancer. The five-year survival rate for pediatric cancer increased from 63% in the 1970s to 87% in 2015-2021, with rates exceeding 90% for certain types. Continued growth will require sustained investment in pediatric cancer research and collaboration.

In 2025, the American Association for Cancer Research (AACR) published its inaugural AACR Pediatric Cancer Progress Report, the first of its kind to focus on advances in pediatric oncology. The report highlights how innovative research has contributed to new U.S. Food and Drug Administration (FDA)-approved therapies, resulting in life-saving treatments for children with cancer.

The report also underscores the challenges that remain. Despite the progress in recent years, cancer remains the leading cause of death in children, and many pediatric cancers lack effective treatment options. Advances have also been uneven across cancer types, leaving some patients with limited options.

Pediatric cancers are fundamentally different from adult cancers, yet funding has not always reflected the unique challenges of studying and treating these diseases. Dedicated research efforts are needed to better understand their underlying biology and develop more effective therapies.

The report also highlights the need for greater investment in rare pediatric cancers, expanded access to clinical trials, and stronger global and public-private partnerships. These efforts could help address disparities in pediatric cancer diagnosis and outcomes.

Sustaining Progress Through Action: New AACR-Kids Beating Cancer Grant

Today, AACR and Kids Beating Cancer launched a new research grant to support pediatric leukemia research. The grant was announced at the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer, held September 22-25 in Philadelphia, and will support research aimed at improving outcomes for children with high-risk acute myeloid leukemia (AML) subtypes.

“Through this grant, we will support innovative research that advances our understanding of pediatric leukemia and other childhood cancers,” said Annie A. Huang, PhD, one of the cochairs of the conference and a senior neuro-oncologist with the Pediatric Brain Tumour Program at the Hospital for Sick Children in Canada. “We are particularly grateful to Kids Beating Cancer for making this opportunity possible and helping us bring new resources to researchers pursing important questions in pediatric cancer.”

Leukemia is the most commonly diagnosed childhood cancer. Approximately 20% of leukemias are AML. Although survival rates for pediatric AML have improved over the past three decades, certain AML subtypes continue to have poorer outcomes. A deeper understanding of these high-risk subtypes could help identify new treatment approaches.

This new collaborative grant honors the legacy of Margaret Guedes, chief executive officer and founder of Kids Beating Cancer, whose son died from AML with monosomy 7, a rare and aggressive subtype. Nearly 30 years ago, Guedes was inspired by her son’s courageous journey and established the nonprofit to support children with cancer and their families. The AACR-Kids Beating Cancer Margaret Guedes Monosomy 7 Legacy Cancer Research Grant will provide $300,000 over three years to support research that will shed light on poorly understood AML subtypes, such as monosomy 7, where significant unmet clinical needs persist.

“This grant will help researchers investigate the unique biology of this disease, identify vulnerabilities that may lead to new therapeutic targets, and address the continuing challenges of treatment resistance and relapse,” said Ian Henrich, PhD, chair of the Kids Beating Cancer Scientific Advisory Board. “We hope this grant becomes a catalyst—by giving an exceptional researcher the resources to translate laboratory discoveries into clinical applications, helping provide more options, more time, and more hope to those affected by this devastating disease.”

Advancing pediatric cancer research requires both bold science and resources to bring promising ideas forward. “We’re bringing together AACR’s scientific leadership and global research community and Kids Beating Cancer’s deep commitment to children and families. Together, we can transform donor generosity into carefully selected, high-impact research with the potential to reach children everywhere,” explained Henrich.

Guedes continued, “Thirty-five years after my son died, we still have no cure for AML with monosomy 7, few effective treatment options, and one of the lowest survival rates among pediatric leukemias. We believe this partnership with AACR will help change that.”

Thanks to advances in prevention, screening, and treatment, cancer mortality has declined over the past decades. Uterine cancer, however, stands as a notable exception, with incidence and mortality on the rise. Now the leading cause of death among gynecologic cancers in the United States according to National Cancer Institute estimates, uterine cancer is projected to claim more lives than ovarian cancer in 2026. This disease remains underfunded, understudied, and associated with deep racial disparities.

To better understand this paradox, we spoke with Elizabeth M. Swisher, MD, the 2026-2028 Chair of the AACR Cancer Prevention Working Group (CPWG) steering committee. She explained why uterine cancer is a growing public health concern in this country and around the world and discussed some of the steps that can be taken to prioritize funding, research, and public awareness.

Under her leadership, the CPWG is advocating for uterine cancer to have its own recognition independent of other gynecologic cancers.

“Just like we don’t talk about prostate cancer and all genitourinary cancers together as one group, the same approach should apply to gynecologic cancers: Cervical, ovarian, and uterine cancer, for example, have completely different screening, prevention, and treatment approaches, so breaking them down is a great first step toward better awareness,” Swisher said.

Swisher is the Torkelson Family Endowed Chair and a professor in the Clinical Research Division of Fred Hutch Cancer Center and in the Division of Gynecologic Oncology of the University of Washington School of Medicine.

What Roles Do Obesity and Hormones Play?

Obesity and metabolic syndrome are the leading preventable risk factors for a portion of endometrial cancers, known as hormone-driven or type 1 endometrial cancer or endometrioid carcinoma, which usually have better outcomes than other subtypes. Obesity rates have risen significantly in the United States over the past several decades, overlapping with and partially driving the increased rates of endometrial cancer. Metabolic syndrome encompasses a cluster of conditions including abdominal adiposity (excess fat around the stomach and lower torso), hyperglycemia, elevated lipids, and hypertension, and is a major risk factor for endometrial cancer in addition to heart disease and diabetes.

Swisher explained that women with more adipose tissue tend to have higher levels of estrogen, the hormone that drives the thickening of the lining of the uterus during the first part of the menstrual cycle. This can create an imbalance with progesterone, which has a protective effect on the uterus. This imbalance stimulates continuous proliferation of endometrial cells, increasing the risk of cancer. Obesity and metabolic syndrome are also associated with insulin resistance and hyperinsulinemia, which can further promote tumor growth.

“Irregular and less frequent periods associated with obesity or metabolic syndrome can be a sign of hormonal dysregulation that will ultimately put the uterine lining at risk for transformation,” Swisher noted. She added that these conditions can manifest in young girls, so having irregular periods is something that should be brought to attention because if it is recognized and modified, it is possible to reduce the risk of endometrial cancer down the road.

In addition to obesity and metabolic syndrome, increased risk for type 1 endometrial cancer is linked to other factors that lead to prolonged exposure of the endometrium to estrogen, including reproductive aspects such as starting periods early, entering menopause later, and never giving birth; conditions like polycystic ovary syndrome; taking tamoxifen to treat breast cancer; and estrogen-only hormone replacement therapy.

Other risk factors for endometrial cancer include older age, a family history of the disease, and Lynch syndrome.

Why Do Black Women Face Worse Outcomes?

Swisher pointed out that uterine cancer exhibits one of the most pronounced racial disparities in cancer outcomes in the country, with Black women being more likely to die from this cancer type than white women despite lower overall incidence.

The excess mortality is mostly driven by higher prevalence of aggressive histologic subtypes among Black women, including uterine serous carcinoma, carcinosarcoma, and clear cell carcinoma. These types of non-endometrioid endometrial cancer or type 2 endometrial carcinoma have a higher mortality than type 1, and disproportionately affects Black women.

“We don’t really know why,” explained Swisher. She hinted to a combination of biological, economic, healthcare-related, and environmental factors. “For example, Caribbean-born Black women have lower risk of endometrial cancer type 2 than Black women born in the United States. This suggests that there may be environmental factors at play, and we need a lot more research to identify the factors that create this disparity.”

Delayed diagnosis is another aspect likely contributing to worse outcomes in Black women. “Partly, that has to do with the fact that the algorithm for how we evaluate abnormal vaginal bleeding was validated in a predominantly white population,” explained Swisher.

The first step for evaluating abnormal bleeding, the hallmark symptom of uterine cancer, is often transvaginal ultrasound that assesses the thickness of the lining of the uterus. Black women have a higher prevalence of uterine fibroids, noncancerous tumors that form in or on the wall of the uterus.

Since these growths can obscure the uterine lining and reduce the test’s ability to detect cancer, ultrasound is less effective as a diagnostic workup for Black women than for white women and may miss cancer. Therefore, an endometrial biopsy is the gold standard, explained Swisher: “It is a minimally invasive procedure that can be easily done during an office visit.”

Community awareness about normal and abnormal bleeding is critical, she added. “If women have been brought up to think that it is normal to bleed well into their 60s, because their mother and their aunts had this type of bleeding due to fibroids, this early sign of cancer won’t be recognized,“ she said.

Rising Deaths, Limited Research Dollars

Despite the increasing trends in incidence and mortality, uterine cancer research receives less funding than other cancer types, Swisher noted.

“I think the underfunding of uterine cancer research is a symptom of the underfunding of women’s healthcare in general. There are other benign conditions that affect the uterus that are massively underfunded, such as uterine fibroids, endometriosis, pelvic pain, and abnormal bleeding. All these conditions are very common but do not receive sufficient attention,” Swisher said. “The uterus, in particular, is something we tend to ignore because we’ve been taught for most of our lives to not talk about our periods and not talk about healthy reproductive function. I think there should be more focus on reproductive health not restricted to childbearing but encompassing all the reproductive organs and functions throughout the lifespan of a woman.”

Swisher partly attributed the funding gap to the fact that uterine cancer outcomes are worse for Black women, a population whose health care issues have been historically underfunded.

What Can Women Do to Reduce THeir Risk of Uterine Cancer?

When detected early, uterine cancer is highly curable, with a five-year survival rate greater than 86%. However, survival drops drastically to less than 20% for advanced-stage disease. Therefore, prevention and early detection are critical.

“A healthy body weight and exercise are important goals to reduce risk. Regular gynecologic care and recognition of abnormal bleeding patterns are also crucial,” said Swisher.

The most common warning sign of uterine cancer is abnormal vaginal bleeding. Swisher emphasized the importance of education early in life about what normal periods are and what is outside the normal range to help counter misconceptions. “In addition to abnormal bleeding patterns often being normalized by family members or by the patient themselves, some physicians and healthcare providers also tend to ignore women who complain of very heavy bleeding and pain, and they discount those symptoms as ‘bad periods,’” Swisher said.

“Even asking women if their periods are normal might not be enough, because the doctor and the patient might have different definitions of what normal is,” Swisher emphasized. “Having providers ask more specific questions to find out what people’s bleeding patterns are would be helpful.”

Education and awareness are critical during the menopausal transition too. “The most common time when endometrial cancer has a delayed diagnosis is perimenopause because all irregular bleeding at that time is just blamed on the hormonal changes,” said Swisher. She explained that while some variation in the timing of periods is common during the menopausal transition, bleeding in between periods or periods that suddenly become much longer might be a warning sign. “Average age of menopause is around 51, up to 55. Beyond that, no amount of bleeding is normal and should be evaluated.“

Advancing Our Understanding of the Disease and Effective Treatments

The addition of immunotherapy to the therapeutic options for uterine cancer has made a substantial difference, said Swisher.

Along with colon cancer, endometrial cancer has the largest fraction of mismatch repair deficiency (MMRd) and microsatellite instability (MSI) of any solid tumor, molecular features that point to better response to immunotherapy. However, immunotherapy clinical trials for uterine cancer arrived later than for other cancer types, including ovarian cancer, which hasn’t historically been responsive to this approach, Swisher noted.

“I think the lagging in treating MSI-high or MMRd endometrial cancer behind colon cancer is another indication of the lack of attention toward endometrial cancer.”

Clinical trials eventually demonstrated that immunotherapy is beneficial not only for patients with MMRd endometrial cancers, but for non-MMRd cancers as well, in combination with chemotherapy.

“The success of adding immunotherapy to endometrial cancer treatment has not only transformed the field and benefited patients, but it has also helped establish endometrial cancer as a good target for drug development,” noted Swisher. “As a result, there are now more drugs being tested for endometrial cancer, including antibody-drug conjugates and other types of immunotherapy, which I’m excited to see in the future.”

Editor’s note: The CPWG recently launched a LinkedIn page for the group where members can share exciting new findings, new funding opportunities, and upcoming conferences that may be of interest to the cancer prevention community.

With school back in session, take a moment to educate yourself on some of the latest advances in cancer research published in the ten peer-reviewed journals of the American Association for Cancer Research (AACR). This month’s Editors’ Picks include insights into cancer evolution in leukemia, a strategy for overcoming drug resistance, the impacts of the COVID-19 pandemic on cancer care, an investigational treatment for triple-negative breast cancer, and more.

Keep reading for the abstracts of the highlighted studies, and follow the links for the full-text articles, freely available for a limited time.

Journal: Blood Cancer Discovery

RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma

Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks.

Significance: We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.

Learn more about the development and evolution of AML: Bloodlines Series: Mapping the Many Paths of Acute Myeloid Leukemia

Journal: Cancer Discovery

Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma

Despite successful immuno-oncology therapies in other cancers, they have largely failed in glioblastoma (GBM). In this study, natural killer (NK) cells from patients with glioma show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. The abundance of NDUFA9+ NK cells informed patient outcomes. Ndufa9 knockout in NK cells compromised mitochondrial function, antitumor efficacy, and the memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. The decreased α-ketoglutarate/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming by inducing the transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell–based immunotherapy for patients with GBM.

Significance: This study reveals that NDUFA9 deficiency in mitochondrial complex I compromises metabolic fitness and impairs the antitumor activity of NK cells in GBM. We identify the mitochondrial complex I subunit NDUFA9 as a key pharmacologically targetable node for NK cell–based immunotherapy in GBM, leveraging metabolic reprogramming to enhance antitumor efficacy.

A related commentary was published in the September issue, where this article was also featured on the cover.

Journal: Cancer Epidemiology, Biomarkers & Prevention

Impacts of a Public Health Emergency on Cancer Testing Rates, Follow-up, and Cancer Diagnosis: An Evaluation of the COVID-19 Pandemic

Background: Public health emergencies can substantially affect routine health care. Large cancer screening declines during the early months of the COVID-19 pandemic are well documented; however, COVID-19’s impact on follow-up of abnormal screening exams and cancer diagnoses is less reported. We examined the impacts of COVID-19 on the cervical, colorectal, and lung cancer screening processes, within 10 health systems in the Population-based Research to Optimize the Screening Process (PROSPR) consortium.

Methods: PROSPR data were used to calculate: (i) monthly rates of cancer testing and, for pre-COVID and COVID time periods, (ii) proportions of individuals receiving recommended follow-up within 6 months of an abnormal test, and (iii) cancer incidence. Surveys were used to assess the healthcare systems’ local context.

Results: During the first 2 months of the pandemic, cancer testing decreased across all health systems and cancer types (range, 18%–96%). Overall, decreases in monthly rates were followed by rapid recovery to prepandemic rates. The rates of 6-month follow-up of abnormal screening results trended down in the COVID versus pre-COVID periods, as did the diagnosis of new cancers.

Conclusions: Declines in cancer testing in the early months of the COVID-19 pandemic were short term, with at least short-term impacts on diagnostic follow-up and cancer diagnosis. The systems with the smallest decreases were those that both utilized remote screening outreach (e.g., mailed fecal immunochemical test kits) and did not pause that outreach at the start of the pandemic.

Impact: Strategies and policies implemented by healthcare systems during public health emergencies can help minimize disruptions in care.

A related commentary was published in the September issue, where the article was also highlighted.

Learn more about the impact of the COVID-19 pandemic on cancer screening and care: AACR COVID-19 and Cancer Report: Patients, Policymakers, and Researchers Share Their Stories

Journal: Cancer Immunology Research

ADAR1 Deficiency in Pancreatic Cancer Cells Potentiates cDC1 Activation and Promotes Sensitization to Immunotherapy

Pancreatic cancer responds poorly to immunotherapy, primarily due to poor activation of CD8+ T cells and their limited infiltration into the tumor tissue. Strategies to enhance CD8+ T-cell priming and function are therefore critical for improving immunotherapeutic efficacy in pancreatic cancer. The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) plays a pivotal role in maintaining immune homeostasis. In this study, we found that ADAR1 expression positively correlates with pancreatic cancer progression. Depletion of ADAR1 in tumor cells resulted in excessive production of interferon β, which increased the abundance and activation of conventional type 1 dendritic cells. This alteration enhanced CD8+ T-cell recruitment and activation, ultimately sensitizing pancreatic cancer to immunotherapy. Collectively, our findings support ADAR1 inhibition combined with immunotherapy as a promising therapeutic strategy for pancreatic cancer.

Learn more about advances in pancreatic cancer research: Pancreatic Cancer: The Search for an Achilles Heel

Journal: Cancer Prevention Research

Will They Use It? Patient and Provider Acceptance of Chatbot Screening and Counseling for Hereditary Cancer Syndromes in a Geographically Underserved Population

Screening for pathogenic variants (PV) associated with hereditary cancer syndromes has a positive impact on public health by identifying patients at risk of developing the associated cancers. This survey assesses the current practice of screening for hereditary cancer syndromes and the acceptability of chatbot utilization among primary care providers and residents in rural Southwest Virginia. A two-part survey was conducted among primary care providers and residents in rural Southwest Virginia to assess demographics, health practices, genetic screening practices, and interest in chatbot technology in a geographically underserved population. The response rates for the provider and resident surveys were 8.9% and 19.9%, respectively. A total of 66 providers responded to the survey. One third (32.3%) of providers in our study never screen for hereditary cancer syndromes, and almost two thirds (63.1%) screen their patients for cancer syndromes less than half the time. About 77% of providers felt that chatbots would be useful in identifying patients who need testing and directing what testing to order. Surveys of 476 residential responders showed that 81.9% of residents felt that chatbot technology sounds somewhat to very useful for genetic screening and counseling. More than 57% of residents noted that they would feel comfortable with utilizing chatbot technology to discuss results of genetic screening. Residents and their providers in geographically underserved populations are interested in using chatbots to improve access to genetic testing. Implementation of technology, such as chatbots, in these underresourced settings has the potential to amplify access to genetic counseling and testing.

Prevention Relevance: This article describes survey results for acceptability of using chatbots for assessing risk and early detection of PVs associated with hereditary cancer syndromes in a rural population. The results could guide further implementation of technology in assisting with early detection and prevention of hereditary cancer syndromes..

This article was featured on the cover of the September issue.

Learn how artificial intelligence-powered tools may transform clinical care: Eye on AI: AI Agents as Doctors’ Deputies in the Cancer Clinic

Journal: Cancer Research (September 1 issue)

Evolutionary Antifragile Therapy Is a Treatment Strategy to Suppress Drug Resistance by Exploiting Dose–Response Convexity

A population of cells within a tumor can be described as antifragile (the opposite of fragile) if they derive a benefit from fluctuations or perturbations in environmental conditions induced by treatment. Treatment fluctuations could either promote (antifragile tumor) or inhibit (fragile tumor) the evolution of treatment resistance to targeted therapies. In this study, we showed that analysis of the convexity of dose–response curves provided a direct prediction of response to prescribed fluctuations in treatment. Convexity predicted that continuous treatment protocols (i.e., zero prescribed fluctuations in treatment) would outperform uneven protocols when dose response is convex. This theory was applied to predict in vivo response to targeted therapy, and the predictions were validated by experimentally testing high/low intermittent dosing (uneven dosing) and continuous dosing (even dosing) schedules. Convexity (and its inverse, concavity) explained 2 phenomena: Dose response is a convex (fragile) function, but the resistance onset rate is a concave (antifragile) function. Thus, design and validation of alternative treatment schedules maximized response while maintaining prolonged sensitivity to treatment. Together, these analyses provide supporting evidence that fluctuations alter the evolutionary trajectory of tumors in response to targeted therapy, even without altering the cumulative dose. By using this insight to design alternative treatment protocols to limit the evolution of resistance by careful analysis of the dose–response curvature, the study supports the potential of “evolutionary antifragile therapy” as a subtype in the broad class of evolution-based treatment strategies.

Significance: The mathematical method using dose response curvature to determine appropriate treatment dosing that limits the evolution of resistance could facilitate designing dose schedules that optimize tumor response.

A related commentary was published in the September 1 issue.

Journal: Cancer Research (September 15 issue)

KLF4 Promotes a KRT13+ Hillock-Like State in Lung Squamous Cell Carcinoma

Lung squamous cell carcinoma (LUSC) is a basal-like subtype of lung cancer with limited treatment options. Although prior studies have identified tumor-propagating cell (TPC) states in squamous tumors, further work is needed to elucidate the broader landscape of intratumoral heterogeneity within LUSC. In this study, we employed SOX2-driven mouse models, organoid cultures, and single-cell transcriptomic analyses to uncover cell fate diversity within LUSC, identifying a KRT13⁺ hillock-like population of slower-dividing tumor cells characterized by immunomodulatory gene expression signatures. The tumor hillock-like state was conserved across multiple animal and human-derived models and was computationally predicted in the majority of human LUSCs, as well as in head and neck and esophageal squamous tumors. Analysis of the cellular origins of tumor hillock-like states indicated that lung club cells give rise to tumors with luminal hillock-like populations, whereas basal-like TPCs transition into basal hillock-like states, resembling lineage plasticity trajectories of the normal lung. Mechanistically, Kruppel-like factor 4 (KLF4) promoted the KRT13⁺ hillock-like state and contributed to resistance to oxidative stress and platinum-based chemotherapy in vitro. Together, these results provide molecular insights into the lineage plasticity underlying intratumoral heterogeneity within LUSC, offering potential avenues for new therapeutic strategies.

Significance: KLF4 drives a slow-cycling, KRT13+ hillock-like state that is plastic with basal lineages, promoting intratumoral heterogeneity in lung squamous cell carcinoma and conserved across squamous cancers, with potential implications for treatment resistance.

A related commentary was published in the September 15 issue.

Journal: Clinical Cancer Research (September 1 issue)

Efficacy and Genomic Analysis of HER2-Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial

Purpose: Human epidermal growth factor receptor 2 (HER2) mutations occur in 1% to 3% of triple-negative breast cancers (TNBC), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib + trastuzumab (N + T; neratinib 240 mg/day, intravenous trastuzumab 8 mg/kg initially and then 6 mg/kg every 3 weeks). We report final results from the neratinib and N + T TNBC cohorts.

Patients and Methods: Primary endpoint: investigator-assessed objective response rate at first postbaseline tumor assessment (ORR_first); secondary endpoints included confirmed ORR by investigator, clinical benefit rate (CBR), and progression-free survival (PFS); exploratory endpoint included circulating tumor DNA (ctDNA) collected at baseline, during treatment, and at the end of treatment.

Results: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40% [95% confidence interval (CI), 12.2−73.8] for neratinib (n = 10) and 35.3% (95% CI, 14.2−61.7) for N + T (n = 17). CBRs were 40% (95% CI, 12.2−73.8) and 47.1% (95% CI, 23−72.2), respectively; median PFS times were 2.89 (95% CI, 0.95−5.52) and 6.24 months (95% CI, 2.10−8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase in on-pathway (ERBB3) and off-pathway (KRAS and TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation.

Conclusions: N + T in patients with HER2-mutant metastatic TNBC seemed to prolong responses versus neratinib alone, representing a novel approach for patients with biomarker-defined metastatic TNBC. Based on these and previously published data, neratinib-based combinations are endorsed by the National Comprehensive Cancer Network guidelines for patients with hormone receptor–positive or –negative metastatic breast cancer with activating HER2 mutations.

A related commentary was published in the September 1 issue.

Learn more about the treatment of TNBC: Experts Explore How to Treat Each Stage of Triple-negative Breast Cancer

Journal: Clinical Cancer Research (September 15 issue)

The First-in-Human ENCIT01 Trial Comparing Second- versus Third-Generation L1CAM-specific CAR T Cells in Patients with Primary Refractory or Relapsed Neuroblastoma

Purpose: Outcomes for children with relapsed and refractory neuroblastoma are dismal. ENCIT-01 (NCT 02311621) was a first-in-human clinical trial for patients with relapsed and refractory neuroblastoma using chimeric antigen receptor (CAR) T cells targeting L1CAM, an adhesion molecule that is overexpressed in neuroblastoma with limited normal tissue expression.

Patients and Methods: This trial evaluated three different CAR constructs: a short-spacer second-generation 4-1BB CAR (2GS, arm A), a short-spacer third-generation 4-1BB + CD28 CAR (3GS, arm B), and a long-spacer second-generation 4-1BB CAR (2GL, arm C).

Results: Thirty-six patients were enrolled, of whom 22 were treated (arm A/2GS n = 11, arm B/3GS n = 8, and arm C/2GL n = 3). Thirty-four of 36 patients had a CAR T-cell product successfully manufactured. Cytokine release syndrome, skin rash, and hyponatremia were common ≥ grade 2 toxicities. Hyponatremia was dose-limiting in three patients [dose level (DL); DL5 arm A/2GS, DL3 arm B/3GS, and DL2 arm C/2GL]. Patterns of toxicity appeared at lower DLs on arms B and C compared with arm A, suggesting differential potency of the third generation and long-spacer products. No objective responses were seen. Correlative analyses demonstrated CAR T-cell presence in tumor and skin, with evidence of macrophage tumor infiltration.

Conclusions: Although feasible to manufacture in a heavily pretreated population, L1CAM may not be an appropriate target in neuroblastoma. Additional engineering strategies may be needed to prevent toxicity and provide durable antitumor effects.

This article was featured on the cover of the September 15 issue.

Journal: Molecular Cancer Research

Archetype Analysis of Lung Adenocarcinoma Premalignancy Links Heterogeneity in Premalignant Lesions to Diverging Features of Invasive Disease

Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is a heterogeneous disease with highly variable histopathologic features and clinical outcomes. LUAD premalignant lesions (PML) are localized proliferations of atypical pneumocytes that spread along the alveolar walls. In this study, we characterized the molecular heterogeneity across PMLs, regardless of histologic classification, and identified four distinct groups or “archetypes” of PMLs using bulk RNA and DNA exome sequencing data from laser-captured microdissected PMLs, normal, and tumor tissues from LUAD resection cases. The archetypes were defined by recurrent gene coexpression modules discovered using the LUAD PMLs we profiled and three publicly available datasets. One PML archetype, termed “proliferation,” was associated with increased expression of genes involved in cell proliferation, a protumor immune environment, and enrichment for EGFR driver mutations. In contrast, the “normal-like” archetype exhibited molecular features similar to normal tissue, an antitumor immune response, and lacked driver mutation enrichment. We projected the PML archetypes into independent gene expression datasets profiling LUAD and found that tumors closest to the proliferation archetype were enriched for multiple features of aggressive LUAD, including high tumor grade and lymph node invasion, and were significantly associated with shorter disease-free survival. Proliferation archetype PMLs may represent a subset of lesions with increased malignant potential and may provide opportunities to improve patient stratification and identify novel targets for lung cancer interception.

Implications: Molecular signatures that distinguish indolent from aggressive LUAD PMLs may help personalize lung cancer screening and interception protocols.

This article was highlighted in the September issue.

Journal: Molecular Cancer Therapeutics

A Bispecific Anti-Fluorescein × Anti-CD3 T-cell Engager in Combination with Fluoresceinated Adaptors Enables Lysis of AML Cells

Tumor-targeting antibodies, antibody–drug conjugates, and radionuclide antibody conjugates are established therapeutic tools in clinical use. Furthermore, bispecific T cell–engaging antibodies (TCEs) and chimeric antigen receptor (CAR) T cells are becoming the clinical standard of care in hemato-oncology and in some solid tissue neoplasms. To allow for on–off switching and targeting of multiple antigens, CAR T cells designed to recognize tumor-bound adaptor molecules (adaptor-CAR T cells) are now being investigated in clinical trials. We hypothesized that like adaptor-CAR T cells, a bispecific TCE recognizing CD3ε on T cells and fluorescein on tumor-bound adaptors would be able to direct T cells against target cells, potentially enabling multiplexing. We here show that a newly generated single-chain Fv-based anti-CD3 × anti-FITC construct (AdFITC-TCE) activates T cells toward acute myeloid leukemia (AML). Recognition of multiple targets through binding to fluoresceinated antibody constructs against CD33 and CD117 enables efficient tumor cell lysis in vitro. Moreover, we demonstrate that AdFITC-TCE plus fluoresceinated adaptors and T cells inhibit AML cell growth in NOD.Cg-Prkdc^scid Il2rg^tm1WjI/SzJ mice in vivo with similar efficacy as AdFITC-CAR T cells. Together, these data suggest that AdFITC-TCE, in combination with any given fluoresceinated binder, might be a versatile tool to activate T cells, leading to respective target cell lysis.

This article was highlighted in the September issue.

Learn about bispecific T-cell engagers: Taking a BiTE Out of Cancer

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Journal: Cancer Research Communications

Glioblastoma Subtypes Exhibit Distinct Migration Mechanics and Immune Responses

Glioblastoma (GBM) remains a deadly cancer driven in part by invasion of tumor cells into the brain. Transcriptomic analyses have identified distinct molecular subtypes, but mechanistic differences that account for clinical differences are not clear. In this study, we show that, as predicted by the motor-clutch model of cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared with proneural cells. Despite their rapid migration and comparable proliferation rates in vitro, mice with mesenchymal tumors survive longer than those with proneural tumors. This improved survival correlated with an immune response in mesenchymal tumors, including T cell–mediated. Consistently, inducing mesenchymal tumors in immunodeficient mice resulted in shorter survival, supporting a protective immune role in mesenchymal tumors. Thus, mesenchymal tumors have aggressive migration but are immunologically “hot,” which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies.

Significance: This study highlights new mechanical and immunologic insights into GBM molecular subtypes using an integrated modeling–genome engineering strategy, which can potentially facilitate GBM subtype-specific therapeutic strategies.

A quarter century has now passed since September 11, 2001, a date that continues to live in infamy—an infamy that, increasingly, is remembered in the same abstract manner as other episodes in the sprawling tide of history.

But the effects of the 9/11 attacks still define lives, especially those of the first responders whose health continues to be impacted by the exposures to toxins and irritants they incurred at ground zero. The intervening 25 years since 9/11 have indeed allowed the biological insults of the attacks to transform into detrimental health effects—including cancer.

On the 25th anniversary of the attacks, Cancer Epidemiology, Biomarkers & Prevention has published a new study investigating cancer incidence among responders who were there that fateful day, as well as those who participated in the cleanup that followed. In memory of those who lost their lives or families on September 11, 2001, this edition of Cancer Research Catalyst reviews the effects of the attacks and showcases the new research being conducted in the 9/11-responder population.

Falling Towers, Rising Carcinogens

Cancer Research Catalyst covered the relationship between the attacks and cancer in 2022, and, as discussed in that post, the debris from the attacks have been associated with increased risks of thyroid cancer, prostate cancer, and possibly leukemia and lymphoma in the first responders who were exposed to the dust and smoke from the collapse of the World Trade Center.

One persistent throughline that should be noted, however, is the role of heightened awareness and screening in identifying these cases. As discussed in the 2022 blog post, the proactive screening efforts among individuals who were at ground zero on 9/11 could, by creating a relative increase in cancer detection, explain some of the observed increased cancer incidence.

However, there is solid evidence that the toxic dust and smoke that choked lower Manhattan was indeed quite toxic in and of itself. The authors of a 2025 study published in Cancer Discovery note that the towers’ collapse led to a massive proliferation of airborne carcinogens and genotoxic substances.

Additionally, their paper showed that 9/11 first responders experienced elevated levels of clonal hematopoiesis, an abnormal expansion of mutated blood cells that can be a precursor of a hematological cancer.

Clonal hematopoiesis can increase as a function of standard aging, but the Cancer Discovery paper found that younger 9/11 first responders demonstrated clonal hematopoiesis that was elevated for their age and notable for the inclusion of mutations in DNA damage repair pathways. The first responders with clonal hematopoiesis had odds of developing leukemia that were more than five times higher than their counterparts without clonal hematopoiesis.

Multiple Primary Cancers in 9/11 Responders

In the newly published study from Cancer Epidemiology, Biomarkers & Prevention, the authors tackled the question of multiple primary cancers among responders to the 9/11 attacks. Multiple primary cancers—two or more distinct, unrelated cancers that occur within the same person—tend to affect cancer survivors more than the general population.

Led by Emanuela Taioli, MD, PhD, who serves as the director of the Institute for Translational Epidemiology at Mount Sinai’s Icahn School of Medicine, the researchers compared the incidence of multiple primary tumors in 4,815 male 9/11 responders from the World Trade Center Health Program who had at least one primary cancer against the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program cohort of cancer patients.

Standardized for age, the proportion of responders with multiple primary cancers was 84% higher than the general SEER population. This was especially pronounced among the responders who received their first cancer diagnoses at younger ages.

Responders who were first diagnosed with cancer between ages 20 to 44 had a proportion of multiple primary cancers that was 3.76 times higher than their counterparts in the SEER cohort. This effect continued at a weaker level in those first diagnosed between ages 45 and 54—among whom first responders had a proportion of multiple primary cancers that was 36% higher than SEER patients—but the effect inverted for those who were diagnosed at age 65 and older. These older first responders had a proportion of multiple primary cancers that was 21% lower than SEER patients.

As time goes by, the exposures that responders experienced may continue to increase their risk for developing cancers.

Thankfully, the James Zadroga 9/11 Health and Compensation Act of 2010 established the World Trade Center Health Program, which provides free medical care for 9/11-related conditions to all responders and survivors of the attacks through the year 2090.

The 9/11 attacks may be a quarter-century past, but their effects continue the shape the world we live in—especially the worlds of those whose heroism has cost them their health.

The following declaration is unlikely to make headlines, but the fact bears repeating: Smoking cigarettes causes cancer.

This wisdom has been well-absorbed. Cigarette smoking, especially youth smoking, remains at an all-time low in the United States. If there are any increases in youth smoking, they have yet to appear in the federal data. Message received, right?

Yes—mostly. We’re reupping the perhaps-obvious fact that cigarette smoking is wildly unhealthy and carcinogenic not just because good advice is timeless (though it is). An ethereal wind of tacit pro-cigarette sentiment has been blowing through the culture lately, aided by the powerful influence of depiction—which has been rising in media, including in top-grossing films (even those rated for young people).

The U.S. Surgeon General does not mince words on the subject. The Surgeon General’s official stance is that the relationship between smoking’s depiction and smoking’s practice is not just correlative; rather, cigarette smoking in top-grossing films directly and actively causes more young people to take up smoking.

As more media consumption takes place on streaming services—platforms where the depictions of tobacco use can occur more than twice as often than on traditional broadcast television—more young people may be induced to start smoking cigarettes or use other tobacco products. And it doesn’t take a scientific analysis to note that popular streaming-service offerings frequently include period pieces—shows in which cigarette smoke sometimes seems to outcompete every other element in the Earth’s atmosphere.

Perhaps as a function of this concerning trend, a slew of recent stories in major outlets have investigated or outright declared smoking as the emergent vice of choice for Generation Z, from the Financial Times to Scientific American to The New York Post.

As young people across the United States return to classrooms and college campuses—forums where the temptation to light up may arise among those who wish to burnish their countercultural bona fides—a review of smoking’s dangers feels warranted amid anecdotal upticks in cigarettes’ visibility among celebrities and smoking’s supposedly revived chic factor among the young.

Cancerous But Cool? Perceptions of Cigarettes’ Aesthetics

Despite cigarette smoke’s well-documented dangers, many people still see an appeal to smoking. If nobody did, it would be difficult to account for the nearly 18.7 million U.S. residents who smoke on a daily basis. Even if they have come to resent the habit (and many do, often saying they wish they’d never begun), smokers have to start somewhere.

One of those appeals, perpetuated in the coverage of Generation Z’s alleged interest in smoking, is the persistent belief among some that cigarettes lend their users an aura worth emulating. This puzzling phenomenon—the idea that a habit so deleterious to one’s health as smoking could be considered cool—is potentially explained by findings that purely aesthetic renderings of smoking can lead directly to cigarette use and addiction.

The relationship between cigarettes in movies and smoking behavior goes back decades. A study published in Cancer Epidemiology, Biomarkers & Prevention in 2009 found that the likelihood of adolescents ever experimenting with cigarettes increased as they were exposed to more smoking depictions in movies—an effect that was especially pronounced in Mexico-born youth, who had 58% higher odds of initiating smoking if they were exposed to smoking imagery via cinema.

Alas, for the film enthusiasts who might enjoy taking in the grey-blue curlicues of the smoldering cigarettes of “In the Mood for Love” or Clint Eastwood’s trademark cigarillo in “The Good, The Bad, and The Ugly,” such imagery comes with temptation to be resisted.

A Carcinogenic Catch-up: How Smoking Causes Cancer

By way of review, smoking causes cancer by introducing carcinogenic compounds directly into the mouth, airway, and lungs. The National Cancer Institute (NCI) reports more than 250 noxious chemicals in cigarettes, of which at least 69 are known to be carcinogenic—including arsenic, benzenes, polycyclic aromatic hydrocarbons (PAHs), and even the radioactive element polonium-210.

At the cellular level, these compounds wreak biological havoc by damaging DNA, which, in turn, triggers a cascade of mutations, inflammation, and oncogenic signaling. As early as the 1950s, scientists observed the toxic effects of cigarette smoke on cellular biology. A 1953 study published in Cancer Research showed that 44% of mice exposed to cigarette-tar condensate developed proven carcinomas—compared with 0% in the control group. In 1964, the U.S. Surgeon General released the landmark report establishing the causal link between cigarettes and cancer.

These biological insults, though they do indeed heavily impact the lungs, don’t just cause lung cancer. The 2025 edition of the Cancer Progress Report from the American Association for Cancer Research (AACR) lists a plethora of cancers caused by smoking tobacco, which collectively account for nearly the entire human body.

No amount of tobacco is healthy. Smoking even a single cigarette exposes users to more than 7,000 chemicals, and the nicotine addiction that cigarettes engender in smokers can drive decades of sustained use.

Because quitting smoking is so notoriously difficult—the majority of U.S. smokers say they want to quit, but fewer than 10% are able to do so—combatting cigarettes’ addictive capacity is a key concern for public health. A paper published in Clinical Cancer Research by members of the AACR Tobacco Products and Cancer Subcommittee outlined the benefits offered by a federal proposal to limit nicotine in combustible tobacco products, which the authors stated would likely prevent millions of deaths if enacted.

Smoking Status: A Sustained Downward Trend

The unequivocal good news is that smoking prevalence in the United States has never been lower. After peaking in 1965 at 42.4%, the U.S. smoking rate has fallen to only about 9.9% of all U.S. adults, according to the Centers for Disease Control and Prevention (CDC). Lung cancer incidence has also followed a downward trend (albeit a more recent one), peaking in the United States in 1992 at 66.4 cases per 100,000 but falling to 43.4 per 100,000 as of 2023, according to the NCI.

These declines have been especially pronounced among the young adult population of the United States. For individuals aged 15 to 39, lung cancer incidence more than halved from 1975, when 2.2 lung cancer cases occurred per 100,000, to just 0.7 cases per 100,000 in 2021.

And despite coverage of a supposed resurgence in smoking’s vogueishness among the young, the current data do not indicate any increases among U.S. young adults. The NCI’s Cancer Trends Progress Report shows that smoking in adults aged 18 to 24 has continued a steep decline, falling by an average of 15.36% every year from 2014 to 2023.

So far, the only blinking warning light in the smoking data is the slowdown of smoking declines in several countries; these are not, however, outright trend reversals. Lung cancer incidence has somewhat rebounded recently among the young, jumping from the all-time low of 0.7 cases per 100,000 in 2021 for those aged 15 to 39 to 1.1 cases per 100,000 in 2023 (a 57% increase in just two years). But the factors that could potentially explain this uptick are myriad and overlapping, and rates of early-onset cancers are increasing in general.

Certain populations do continue to smoke at rates higher than the all-U.S.-adult baseline. As of 2022, when 11.6% of all U.S. adults reported smoking daily, smoking rates were higher in those aged 45 to 64 (14.9%); lesbian, gay, and bisexual adults (15.3%); adults with low annual household income (18.3%); and those with a GED as their highest educational attainment (30.1%—the highest reported smoking rate of any group within the dataset). These disparities are due in no small part to societal factors, including documented, long-standing targeted advertising efforts by tobacco companies.

Kinda Quitting: The Vaping Transition

E-cigarettes and nicotine-vapor devices (vapes) are being used by some as quitting aids that rank lower than cigarettes on what researchers describe as nicotine’s “continuum of risk.” However, none of these products has been approved by the U.S. Food and Drug Administration (FDA) as a way to stop smoking or quit other tobacco products. Proven tobacco cessation strategies exist, supported by the resources of federal, state, and local governments—and these recommended cessation strategies do not include vaping.

Additionally, vaping has become a vice unto its own, increasing sharply among U.S. adults—of whom 7% vape—and especially among youth. Though mitigation efforts have attenuated its prevalence among adolescents, U.S. high school students still continue to vape at a rate of 7.8% as of 2024.

One study found that, among students from 8th to 12th grade who vape daily, the rate of unsuccessful quit attempts has risen from 28% to 53%. And vape use is by no means a middle- and high-school phenomenon; a concerning 15.5% of young adults aged 21 to 24 engage in the practice as of 2023. Problematically, people who take up vaping in an attempt to quit smoking may end up as dual users of both tobacco products, an outcome associated with comparably negative outcomes as smoking alone.

It is currently unclear whether vaping causes cancer; carcinogenesis typically takes years, and the rise of e-cigarette use is too recent for the data to be clear. However, vaping is clearly harmful. As the CDC says, “No tobacco products, including e-cigarettes, are safe, especially for children, teens, and young adults.”

Like their tobacco leaf antecedents, vapes also induce cell-level biological changes and contain a significant number of carcinogens—which suggests that, once data are mature, clearer links between vaping and cancer may emerge. One study published in Cancer Research showed that cell samples taken from both smokers and vape users with limited smoking histories shared changes consistent with lung cancer development; similar results have been replicated in other studies.

Vapes’ popularity among young people is likely due to the appeal of the flavoring agents that can make the addictive nicotine vapor taste like just about anything—from menthol to candy bars. One study found that the overwhelming majority of young vape users (89.4%) used flavored products, among which the most popular were designed to taste like fruit or desserts.

Most of these flavored products are illegal, despite the FDA’s 2026 authorization of a limited number of flavored vapes. But incomplete enforcement has allowed these youth-targeting products to remain on shelves. And it’s not just the flavors’ appeal that poses a threat—the chemical compositions of the flavoring agents may carry intrinsic risks of their own. One chemical analysis found that flavored nicotine vapor, compared with unflavored vapor, contained significantly more acetaldehyde (a possible carcinogen), acrolein (a probable carcinogen), and formaldehyde (a known carcinogen).

Other new tobacco products like nicotine pouches are also rapidly increasing in usage, and while less overtly dangerous than cigarettes, they present new potential for people of all ages, but particularly youth, to become or stay addicted to tobacco products—and experience negative health outcomes as a result.

The Best Time to (Not) Start Is Now

Long gone are the days of Joe Camel and his cigarette-promoting ilk thanks to federal restrictions on cigarette marketing, and for whatever the buzz about a cigarette comeback in the zeitgeist, smoking remains at historic lows. However, the use of new tobacco products is becoming increasingly prevalent; the trend, much like the unwelcome smolder of a lit cigarette, can and should be extinguished.

For those who don’t smoke, the habit is not worth picking up. Similarly, the use of e-cigarettes or nicotine pouches is also harmful and addictive. Anyone who does not use a tobacco product should not start—regardless of how suave media depictions may make it seem. For those who do smoke: It is no exaggeration to say that quitting may be lifesaving. The resources for those who wish to quit are ample; learn more about tobacco cessation at smokefree.gov.