Cancer medicine has never been more powerful, or more complex. Modern drugs can melt tumors that once seemed unbeatable, and survival rates for many cancers keep climbing. Yet while newer treatments often have preferable side effect profiles compared to chemotherapy, they can affect some of the body’s most vital organs, including the heart.

Cardiotoxicity can come in many forms, and sometimes does not manifest until decades later, something Peter Wolf learned after a yearslong quest for answers related to valve disease rooted in radiation treatment for lymphoma in his teens.

Cancer and cardiovascular disease already claim the top two spots on the U.S. mortality list, and cancer survivors face about a 42% higher risk of heart problems compared with people who have never had cancer. The ultimate goal is not a Pyrrhic victory but a lasting one: eliminate the cancer and let patients enjoy a better quality of life with healthy hearts.

The Importance of Healthy Cardiovascular Highways

Think of the endothelium—the single-cell layer lining every artery, vein, and capillary—as the pavement of the body’s circulatory highways. When healthy, it keeps blood (and the circulating immune cells) gliding smoothly where they need to go, widening or narrowing lanes as necessary and preventing fender benders that could clog the road. But new generations of treatments for chronic myeloid leukemia (CML) can turn parts of a once-smooth pavement into hazard-filled stretches with potholes prone to pileups and clots.

Approved in 2001, imatinib (Gleevec) became the first small molecule precision therapy, and created a new class of treatments known as tyrosine kinase inhibitors (TKIs). Instead of indiscriminately targeting dividing cells, imatinib homes in on an abnormal fusion protein called BCR-ABL. This protein is created by the Philadelphia chromosome, an accidental DNA swap between two chromosomes that characterizes roughly 95% of CML cases. For many patients, imatinib transformed CML from a deadly disease into a long-term, manageable condition.

But cancer sometimes finds ways to escape; by acquiring BCL-ABL mutations that weaken the grip of imatinib, for example. Enter the next-generation TKIs. These treatments, such as dasatinib (Sprycel), nilotinib (Tasigna), and ponatinib (Iclusig), latch onto BCR-ABL differently and, in ponatinib’s case, can even overcome some mutations that provide resistance against other TKIs. However, they can also come with greatly increased risks of heart attack, stroke, or limb-threatening clots.

Why the difference?

According to Iris Jaffe, MD, PhD, the Elisa Kent Mendelsohn Professor of Molecular Cardiology and executive director of the Molecular Cardiology Research Institute at Tufts Medical Center, the trouble traces back to blood vessel inflammation.

At the AACR Annual Meeting 2025, Jaffe highlighted how endothelial cells exposed to ponatinib clung to platelets much more readily, and in mice that develop human-like atherosclerosis when fed a high-fat diet, ponatinib increased inflammation, immune cell trafficking (both T cells and myeloid cells), and unstable fatty plaques.

Most strikingly, ponatinib invariably led to cardiovascular events or death in a novel plaque rupture model, whereas imatinib caused similar fates only 20% of the time. Interestingly, asciminib (Scemblix), a new TKI and the first to target tyrosine kinase enzymes in CML in an allosteric fashion, meaning it doesn’t target the active binding site, led to similar survival rates as imatinib in mice, and also appeared to spare their endothelium.

In follow-up experiments, Jaffe and her colleagues revealed that blocking the inflammatory switch TNFR2 could calm the endothelial lining and protect against cardiovascular events, hinting at the possibility of strategies to neutralize this vascular toll without sacrificing anticancer power.

As far as how the different TKIs affect the signaling of specific tyrosine kinase pathways, no single kinase alterations stood out, so the team sought to capture the “fingerprints” left behind by different TKIs that reflect how they influence kinase activity more globally in these endothelial cells. By comparing these TKI fingerprints to those of 30 already approved cardiovascular drugs the researchers hope to identify therapies with opposing signatures that might be able to counteract specific TKI-induced cardiotoxicity, though distinct TKI signatures would likely demand different cardiotoxicity counterbalancing strategies.

Age is another factor that impacts risk, Jaffe noted. CML usually appears after midlife, and consequently, more than 60% of patients already have hypertension, diabetes, or coronary disease at the time of diagnosis. She noted that having just one of those risk factors doubles the likelihood of a drug-induced clot, meaning the treatment that rescues an older patient from leukemia can unmask a silent vulnerability in arteries already under strain.

“The Weakest Link”

Why are endothelial cells so fragile in the first place?

One answer, according to Kristopher Sarosiek, PhD, a principal investigator and associate professor at the Harvard T.H. Chan School of Public Health, might be their unique susceptibility to apoptosis, a built-in program that allows cells to quietly self-destruct if they sustain too much DNA damage, for example.

Picking up the thread where Jaffe left off during the “Cardio-Oncology: A Novel Platform for Investigation” Major Symposium, Sarosiek revealed how he and his colleagues used a method called BH3 profiling to learn that endothelial cells remain “primed” for apoptosis throughout the lifetime of mice. Heart-muscle fibers, liver cells, and other functional (parenchymal) cells, in contrast, seemed to grow tougher with age. That intrinsic sensitivity could explain why chemotherapy and radiation, which can damage DNA, often disrupt the vascular lining first. This makes them, in Sarosiek’s words “the weakest link” when it comes to toxicity.

In young mice—whose endothelial cells, in addition to their heart muscle cells, were particularly primed for apoptosis—the chemotherapy doxorubicin compromised heart function, unless the researchers disabled the BAX/BAK proteins that trigger apoptosis.

Shielding endothelial cells, whether by tweaking drug schedules, adding protective medications, or engineering smarter molecules, could allow doctors to preserve heart health without dialing back cancer-killing potency. To complement those potential solutions in the meantime, biomarkers that help predict who is most at risk of cardiotoxicity would be valuable in guiding vulnerable patients to avoid certain therapies, Sarosiek said.

When the Immune System Misfires on the Heart

Beyond endothelial damage due to cytotoxic drugs, immunotherapies like immune-checkpoint inhibitors (ICIs) can also unleash cardiovascular damage. ICIs unleash T cells by removing molecular brakes such as PD-1 or CTLA-4. While these immunotherapies have been transformative for many types of advanced cancers, in about 1% of recipients they trigger myocarditis, an inflammatory attack on the heart muscle itself.

That 1% looms large, however, as the cardiotoxicity proves fatal in roughly 40% of cases, making ICI-induced myocarditis the most lethal immune-related side effect, according to Javid Moslehi, MD, the University of California, San Francisco (UCSF) William Grossman Distinguished Professor in Cardiology and chief of cardio-oncology and immunology at UCSF Health. In addition to founding the UCSF Myocarditis Center, Moslehi also leads the International ICI-Myocarditis Registry that, as of April 2025, had tracked nearly 1,300 cases from 150 centers across 26 countries.

The registry’s analyses have linked increased risk to combination regimens, in particular the dual administration of ICIs targeting LAG-3 and PD-1. To unravel the biology, Moslehi and colleagues utilized mice missing one copy of CTLA-4 and both copies of PD-1, both crucial immune checkpoints. Every such mouse died of myocarditis, driven by T cells that mistook alpha-myosin, a heart-specific protein, for a target. The other arm of adaptive immunity also plays a role, with a study in the AACR journal Cancer Immunology Research showing that B cells contribute to ICI-induced cardiotoxicity through the production of heart-targeting antibodies.

Standard steroids often prove ineffective in patients with ICI-induced myocarditis, among other hurdles, so Moslehi and his collaborators have been exploring a two-drug, immune-modulating rescue approach previously highlighted on the AACR blog. During this session, Moslehi shared clinical updates from his colleague Joe-Elie Salem, MD, PhD, an associate professor at Sorbonne Université in Paris, that demonstrated a potentially valuable approach for patients with ICI-induced myocarditis: combining abatacept (Orencia), which is used to treat rheumatoid arthritis, with ruxolitinib (Jakafi/Opzelura), a drug with applications in graft-versus-host disease, dermatitis, and vitiligo.

Discussing the study in which myocarditis deaths were limited to about 2% in the first 90 patients using this combination, Moslehi said, “Again, not a randomized trial, but it’s perhaps a cocktail that one could use in our patients.”

Searching for Solutions for Long-term Survivors

Roughly 5.4% of the population in the United States—about 18.6 million people—are cancer survivors. Cardiovascular complications already rank as their second-leading cause of long-term death, and is the leading cause in long-term survivors of breast, colorectal, and prostate cancers. Even modest advances in cardio-oncology could bring huge gains in quality years. As the mechanisms mediating cardiovascular side effects become better understood, doctors will better be able to tailor their care, or at least monitor patients who might be at risk, to intervene early with any necessary countermeasures.

Throughout human history, food has required some degree of processing to make it edible, improve its taste, or prepare it for storage. But with the Industrial Revolution came lifestyle changes and sophisticated technologies that demanded greater convenience and enabled a whole new level of food processing. The food industry was no longer limited to chopping, seasoning, and cooking whole foods. Now, industrially made ingredients could make food more appealing and increase shelf life, all while lowering costs. These advances led to the birth of what we know as “ultraprocessed foods.”

The socioeconomic benefits of ultraprocessed foods are hard to dispute. They’re cheap, quick to prepare, long-lasting, and easy to find—making nutritious foods like whole-grain bread accessible to many Americans who don’t have the time or resources to regularly bake a homemade loaf or to buy one from an artisanal bakery.

The popularity of ultraprocessed foods has continued to rise, and today, they account for nearly 60% of the American diet. Such high consumption, however, has many concerned that these foods could be wreaking havoc on our health.

But does the evidence support this concern?

Are all ultraprocessed foods equally harmful?

And what does “ultraprocessed” mean anyway?

Experts continue to debate these topics, weighing the strengths and limitations of past studies and finding improved ways to study and define this group of foods. The issue has even caught the attention of the federal government, which recently launched the Nutrition Regulatory Science Program to examine the health impacts of ultraprocessed foods and announced that it would develop a new definition of ultraprocessed foods—a step that could have ramifications for a slew of policies and dietary guidelines.

What Are Ultraprocessed Foods?

From peeled vegetables to potato chips, nearly everything we consume is processed—but clearly not to the same extent. To better study the health effects of differentially processed foods, in 2016, Carlos Monteiro, MD, PhD, from the University of Sao Paulo in Brazil, and colleagues developed the now commonly used NOVA classification scale, which categorizes foods into one of four groups based on how processed they are.

Group 1 foods are those that are unprocessed or that have been minimally processed to remove inedible parts and/or to prepare the food for storage. Examples include fresh or frozen fruits and vegetables, meats, grains, eggs, nuts, and seeds.   

Group 2 foods are ingredients used in cooking, such as butter, oil, sugar, vinegar, and salt, among others. Unlike Group 1 foods, these ingredients are not immediately found in nature. Instead, they are derived from Group 1 foods through processes such as churning, extraction, or fermentation. Butter, for example, is produced by churning milk, oils can be extracted from seeds, and vinegar can be produced from fermenting grapes.

Group 3 foods are processed foods produced by combining Group 1 and Group 2 ingredients and, in some cases, have been preserved via canning, bottling, or fermentation. Group 3 foods include sauteed vegetables, cheese, canned beans, and homemade bread.

Finally, Group 4 foods represent ultraprocessed foods, which are generated using ingredients and/or processes not found in a typical home kitchen, such as high-fructose corn syrup or hydrogenated oils. Because these foods are made with lower-quality ingredients, they often include flavorings, artificial colors, and other additives to improve their taste and appearance—things like butylated hydroxyanisole, xylitol, or red no. 40, to name just a few. Examples of Group 4 foods include soda, candy, most fast foods, breakfast cereal, chicken nuggets, lunch meat, packaged breads, plant-based milk, flavored yogurt, and meat substitutes.

How Do Ultraprocessed Foods Impact Health?

Using the NOVA scale, researchers have found correlations between ultraprocessed foods and a variety of metabolic and cardiovascular diseases. As one example, a meta-analysis of 25 studies found that high intake of ultraprocessed foods was associated with an increased risk of diabetes, high blood pressure, obesity, unhealthy cholesterol levels, and high triglycerides. The degree to which the risks increased, however, varied widely between studies due to differences in how each was performed.

Building on this type of correlative data, a randomized trial conducted at the National Institutes of Health by Kevin D. Hall, PhD, and colleagues demonstrated that switching from a minimally processed diet to an ultraprocessed diet increased consumption and weight gain—lending credence to the notion that ultraprocessed foods are not just correlated with obesity but may in fact cause it.

But, as many experts have noted, it is still not known whether the effects are due to the ultraprocessing per se, or just a result of these foods often having higher levels of sugar, salt, and fat. And while some have suggested that ultraprocessed foods could be addictive, a separate study by Hall and colleagues disputed this theory, indicating that alternative factors could be to blame for the common overconsumption of these foods.

Do Ultraprocessed Foods Increase Cancer Risk?

Whether directly or indirectly, the idea that ultraprocessed foods are associated with increased risk of metabolic and cardiovascular diseases is well supported, but what about cancer?

Studies have shown associations between ultraprocessed foods and increased cancer risk, and a meta-analysis found that these foods were, on average, associated with a 12% increased risk of total cancer incidence. However, the association was considered “suggestive” and based on “very low quality” evidence.

Among the individual cancer types examined in the meta-analysis, the researchers reported that only colorectal cancer was consistently associated with consumption of ultraprocessed foods.

As with other diseases, it remains to be seen whether it is the ultraprocessed nature of these foods that increases risk of cancer—for example, through additives or carcinogens derived from food processing methods—or whether the impact is primarily due to the higher levels of fat, salt, and sugar. These components could indirectly lead to cancer by promoting obesity, inflammation, and disruption of the gut microbiome or metabolic processes.

Substitution effects may also be at play, as eating a lot of ultraprocessed foods often means eating fewer of the unprocessed or minimally processed foods known to decrease cancer risk, such as fruits and vegetables.

Another important question is whether ultraprocessed foods as a whole are associated with cancer risk or whether the impact is driven by specific foods.

Interestingly, an analysis by Mingyang Song, ScD, from Harvard University, and colleagues found that high intake of ultraprocessed foods was associated with higher colorectal cancer risk for men but not for women. Song noted that the sex-specific impact could be due, in part, to differences in the types of foods men and women consumed.

“Ultraprocessed food is a very complex mixture of different food groups,” said Song during a presentation at the AACR Annual Meeting 2025, held this past April. “That makes the measurement and risk assessment particularly challenging.”

Certain ultraprocessed foods, including processed meat and sweetened beverages, have been convincingly associated with an increased risk of cancer, but most studies to date have not examined the impact of specific foods or individual ingredients and instead have treated ultraprocessed food as a monolith.

Much of this stems from the indiscriminate way that ultraprocessed foods are defined. Of note, the NOVA classification system is based solely on how processed a food is and does not account for a food’s nutritional value. As a result, foods like store-bought whole-grain breads—which provide fiber, complex carbohydrates, and other nutrients known to decrease cancer risk—are classified in the same category (Group 4) as soda—which has little to no nutritional value and is associated with liver cancer.

Experts argue that this feature of the NOVA system complicates interpreting the risks and benefits of ultraprocessed food consumption and may unfairly demonize otherwise nutritious foods.

“We believe that by considering both the food processing and nutrient profiles, we can better classify ultraprocessed foods,” Song said.

Should We Stop Eating Ultraprocessed Foods?

It’s still up for debate whether we should eliminate ultraprocessed foods from our diets. Some experts recommend limiting their consumption, pointing to the many studies linking these foods to poor health outcomes. Others argue that there isn’t convincing evidence yet to show that ultraprocessing itself, rather than individual ingredients commonly found in these foods, is inherently harmful.

Regardless of their views on ultraprocessing, experts agree on the importance of prioritizing nutritious foods and limiting those high in sugar, salt, and fat, which are linked to many diseases, including cancer.

Experts also agree on the need for more research.

To tease apart the contribution of specific ultraprocessed foods and ingredients on disease risk, researchers need to develop a more nuanced definition of ultraprocessed food that incorporates nutrient profiles, Song said.

In addition, identifying biomarkers of ultraprocessed food consumption and following large cohorts over many years will help researchers better understand the impact on cancer, and studies that examine how dietary changes and other interventions impact cancer risk will be required to demonstrate causality.

Acknowledging some of the lifestyle benefits of ultraprocessed foods, Song noted, “I don’t think it’s realistic for us to eliminate ultraprocessed foods from our diet.”

However, he hopes that “further research to improve the assessment of ultraprocessed foods and identify specific ingredients in ultraprocessed foods that may increase cancer risk … will inform future regulatory and policy changes.”

Douglas Hanahan, PhD, FAACR—the recipient of the 2025 Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research—is no stranger to pivotal moments in oncology. And he thinks we may be on the brink of more breakthroughs against hard-to-treat tumors like uterine cervical cancer and glioblastoma, an aggressive form of brain cancer, thanks to his latest research on finding ways to overcome immunosuppression.

A quarter of a century ago, Hanahan published “The Hallmarks of Cancer,” a conceptual framework that gave researchers a common language for the traits that enable cancers to become malignant. In two subsequent updates, most recently in the AACR journal Cancer Discovery in 2022, he has expanded on the original foundation and incorporated the latest science to help move the field forward. (Read more about each iteration of the hallmarks of cancer in this past blog post.) Hanahan is currently the president emeritus of the Swiss Federal Institute of Technology and a distinguished scholar with the Ludwig Institute for Cancer Research in Lausanne, Switzerland.

In an effort to “move basic cancer biology toward cancer medicine,” Hanahan unveiled two lines of work in his lecture that dive deeper into one of the hallmarks of cancer first acknowledged in the 2011 update: avoiding immune destruction. Specifically, he revealed how tumors sabotage immune responses far beyond their own borders and how an old antidepressant might turn one of oncology’s most intractable cancers into an immunotherapy target.

Short-circuiting Systemic Immunosuppression

The centerpiece of his talk focused on human papillomavirus type 16 (HPV16)-driven cancers, especially cervical cancer. While cervical cancers that express HPV16-specific oncoproteins might seem like ideal candidates for vaccine therapy, Hanahan noted that therapeutic vaccines have often floundered in both mice and humans.

His group suspected the problem lay outside the tumor microenvironment and were a result of systemic immunosuppression. In a Cancer Discovery article published simultaneously during the conference, the team performed multiomic screens of cervical tumor tissue, as well as the bone marrow, spleen, and blood, to identify molecules and pathways that maintain systemic immunosuppression. Three cytokines from the interleukin-1 (IL-1) family leapt out as significant: IL-1alpha, IL-33, and IL-36beta. While these IL-1 family cytokines bind different receptors on the surface of cells, the downstream signaling of all three relies on the IL1RAP coreceptor component expressed mainly by developing neutrophils.

When the IL-1 family trio engages IL1RAP, bone marrow output skews toward neutrophils, spleens swell, and those neutrophils migrate to lymph nodes and tumors where they paralyze the T-cell response a vaccine needs to elicit tumor elimination. In the lab, T cells grown with splenocytes from tumor-bearing mice had significantly reduced proliferation, helping to explain why a vaccine alone is typically ineffective.

Fortunately, blocking IL1RAP can break the spell. A mouse antibody against IL1RAP reduced neutrophil counts, shrank spleens, and—paired with a nanoparticle vaccine targeting the E7 HPV oncoprotein—sparked T-cell infiltration and rapid tumor regression, and significantly improved survival. Somewhat surprisingly, CTLA-4 immunotherapy, but not PD-L1 immunotherapy, widened the survival gap further.

The clinical relevance of this approach looks promising, according to Hanahan, whose team mined data from The Cancer Genome Atlas (TCGA) to build a 10-gene systemic immunosuppression score that included IL-1alpha, IL-33, and IL-36beta, among other molecules. Tumors that scored high—whether cervical, head and neck, or lung cancer—were linked to poorer prognosis, hinting that IL-1-driven systemic immunosuppression may be a common escape route.

 “We believe that a triplet of this HPV16 oncoprotein vaccine, anti-IL1RAP … plus anti-CTLA-4 warrants consideration for clinical trials,” Hanahan concluded.

Early data from a first-in-human trial provides some support, though PD-1 immunotherapy appeared beneficial in this clinical context. When nadunolimab, a humanized antibody against IL1RAP, was combined with PD-1 blockade, elevated neutrophil counts normalized in patients with lung and pancreatic cancers. This positions IL1RAP blockade as a practical path to disarm systemic immunosuppression and potentially enhance the effects of various immunotherapies, though the distinct effects of combinations involving different immune checkpoint inhibitors must be further clarified.

Antidepressant Flips Macrophages’ Mood Against Tumors

Hanahan next offered a glimpse into cancer neuro-immunology. His lecture’s closing act shifted to glioblastoma, where imipramine, a 60-year-old tricyclic antidepressant, emerged as an unlikely ally. In mouse glioblastoma models, the antidepressant turbocharged autophagy in tumor cells and flipped macrophages from a tumor-supporting to a tumor-attacking state.

Combined with VEGF blockade, the drug normalized aberrant blood vessels and cleared a path for adaptive immune cells to more efficiently enter tumors. Yet most mice eventually relapsed, until an anti-PD-L1 antibody was added to the mix. The triple therapy flooded tumors with T cells and doubled survival compared to the antidepressant plus VEGF inhibition. A Swiss pilot study, PHENIX, will soon test imipramine, the VEGF-A antibody bevacizumab (Avastin), and the anti-PD-1 antibody cemiplimab (Libtayo) in patients with recurrent glioblastoma.

Both stories extend Hanahan’s original hallmarks. Immune evasion is not just a skirmish at the tumor rim; it can be a body-wide blockade or a brain-tuned switchboard. But each defense reveals a seam: IL1RAP antibodies for HPV cancers, an antidepressant-anchored cocktail for glioblastoma. For a scientist whose frameworks have guided oncology for decades, the 2025 Pezcoller Foundation-AACR International Award lecture felt less like the closing of a chapter than the opening of a new front in the effort against cancer.

Summer is heating up, so why not keep cool by reading about some of the hottest topics in cancer research? This month’s Editors’ Picks from the 10 peer-reviewed journals of the American Association for Cancer Research (AACR) include studies on pancreatic cancer interception, breast cancer risk prediction, the tumor microenvironment, and more.

Read the abstracts of the selected articles below, and follow the links to access the full-text articles, freely available for a limited time.

Journal: Blood Cancer Discovery

A Model of Intratumor and Interpatient Heterogeneity Explains Clinical Trials of Curative Combination Therapy for Lymphoma

Models of tumor drug response have illuminated important concepts in oncology, but there remains a need for theory that combines intratumor and interpatient heterogeneity to explain patient outcomes, especially for curative treatments. In this study, we present a mathematical model of multidrug therapy that describes both cell-to-cell and patient-to-patient heterogeneity as distributions of drug sensitivity and apply it to simulate curative combination therapies for diffuse large B-cell lymphoma (DLBCL). Simulated trials reproduced progression-free survival and changes in ctDNA observed under standard therapy and accurately predicted success or failure of nine randomized trials of first-line combinations based on drug efficacies in relapsed/refractory DLBCL. Finally, we used the model to explore how drug synergies, biomarkers, and subtype-specific endpoints could improve the chance of success of targeted combination therapies. This study offers a quantitative model of curative drug combinations and suggests that predictive simulations could aid the design of new regimens with curative intent.

Significance: A new model of intratumor and interpatient heterogeneity in response to drug combinations explains and predicts the results of clinical trials of curative-intent treatments for DLBCL. This model can be used to understand and inform optimal design of curative drug combinations and clinical trials.

A related commentary was published in the May issue.

Journal: Cancer Discovery

Long-Term Latency of Highly Mutated Cells in Normal Mouse Skin Is Reversed by Exposure to Tumor Promoters and Chronic Tissue Damage

Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. In this study, we carried out whole-genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues.

In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.

Significance: Using historical skin cancer models, we reveal that mutated cells can persist without tumor formation and give rise to cancer upon exposure to tumor promoters, underscoring the importance of tumor promotion over initiation as the rate-limiting step in carcinogenesis and the need for cancer prevention strategies targeting promotional factors.

This article was featured on the cover of the June issue, which also included a related commentary.

Journal: Cancer Epidemiology, Biomarkers & Prevention

The Breast Tumor Immune Microenvironment of DNA Double-Strand Break Repair Pathogenic Variant Carriers Is Enriched with Tumor-Associated Macrophages

Background: Approximately 5% of patients with breast cancer have a rare pathogenic germline genetic variant that is associated with increased breast cancer risk. Mutations in more than 12 genes have been associated with hereditary breast cancer risk, many of which are involved in genome stability pathways, including DNA double-strand break (DSB) repair. We hypothesized that carriers of DSB repair–related pathogenic variants (PV) may have a distinct tumor immune environment that differs from that of noncarriers.

Methods: We utilized tumor transcriptome data from 559 participants with invasive breast cancer from the Nurses’ Health Studies and Nurses’ Health Studies II to infer immune-related gene expression signatures and immune cell abundance.

Results: Thirty-three (5.9%) individuals had germline DSB repair–related PVs in one or more of the following genes: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FANCC, FANCM, NBN, PALB2, RAD50, RAD51C, and/or RECQL. In covariate-adjusted analyses, DSB repair–related PV carrier status was positively associated with both a STAT1 signature (standardized β = 0.59; P = 3.5 × 10⁻³) and inferred M1 macrophage infiltration (standardized β = 0.56; P = 1.4 × 10⁻³). Furthermore, these immune features correlated with other features related to tumor IFN response signaling, suggesting that this enrichment is occurring in an inflammatory context.

Conclusions: These results indicate that breast tumors of DSB repair–related PV carriers have distinct immune features, which may have therapeutic implications in this high-risk population.

Impact: These results support further characterization of macrophage characteristics and abundance in the breast tumor microenvironment of DSB repair–related PV carriers.

Journal: Cancer Immunology Research

Mesenchymal Stem Cells and Fibroblasts Contribute to Microvascular Proliferation in Glioblastoma and are Correlated with Immunosuppression and Poor Outcome

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45⁻CD105⁺ vascular/perivascular stromal cells (PVSC) and CD45⁺CD105^± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45⁻CD105⁺ compartment. RNA velocity analysis identified PDGFRB as a putative driver gene guiding mesenchymal stem cells toward more mature PVSCs in the context of MVP. Signaling network analysis and digital spatial profiling uncovered interactions between PDGFRB⁺ PVSCs and immunosuppressive myeloid cell subsets enriched in the perivascular niche, suggesting targetable receptor–ligand interactions. Additionally, a gene signature of MVP-associated PVSCs from gliomas predicted worse prognosis in multiple other solid tumors. This study provides a transcriptomic cell atlas of PVSCs and immune cells in glioma, helping to refine the biological model of MVP which has traditionally focused on endothelial cells.

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

Journal: Cancer Prevention Research

Deriving a Mammogram-Based Risk Score from Screening Digital Breast Tomosynthesis for 5-Year Breast Cancer Risk Prediction

Screening digital breast tomosynthesis (DBT) aims to identify breast cancer early when treatment is most effective, leading to reduced mortality. In addition to early detection, the information contained within DBT images may also inform subsequent risk stratification and guide risk-reducing management. Using transfer learning, we refined a model in the Joanne Knight Breast Health Cohort at Washington University, a cohort of 5,066 women with DBT screening (mean age, 54.6), among whom 105 were diagnosed with breast cancer (26 ductal carcinoma in situ). We applied the model to external data from the Emory Breast Imaging Dataset, a cohort of 7,017 women free from cancer (mean age, 55.4), among whom 111 pathology-confirmed breast cancer cases were diagnosed more than 6 months after initial DBT (17 ductal carcinoma in situ). We obtained a 5-year AUC of 0.75 [95% confidence interval (CI), 0.73–0.78] in the internal validation. The model validated in external data gave an AUC of 0.72 (95% CI, 0.69–0.75). The AUC was unchanged when age and Breast Imaging-Reporting and Data System density were added to the model with synthetic DBT images. The model significantly outperforms the Tyrer-Cuzick model, with a 5-year AUC of 0.56 (95% CI, 0.54–0.58; P < 0.01). Our model extends risk prediction applications to synthetic DBT, provides 5-year risk estimates, and is readily calibrated to national risk strata for clinical translation and guideline-driven risk management. The model could be implemented within any digital mammography program.

Prevention Relevance: We develop and externally validate a 5-year risk prediction model for breast cancer using synthetic DBT and demonstrate clinical utility by calibrating to the national risk strata as defined in breast cancer risk management guidelines.

Journal: Cancer Research (June 1 issue)

FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development

Activating KRAS mutations are a key feature of pancreatic ductal adenocarcinoma (PDAC) and drive tumor initiation and progression. However, mutant KRAS by itself is weakly oncogenic. Defining the pathways that cooperate with mutant KRAS to induce tumorigenesis could identify prevention and treatment strategies. Analyzing organoids and murine and human pancreatic specimens, we found that the receptor tyrosine kinase FGFR2 was progressively upregulated in mutant KRAS-driven metaplasia, precancerous lesions, and classical PDAC. In genetic mouse models, FGFR2 inactivation impeded mutant KRAS-driven transformation of acinar cells by reducing proliferation and MAPK pathway activation. FGFR2 abrogation significantly delayed tumor formation and extended the survival of these mice. Furthermore, FGFR2 collaborated with EGFR, and dual blockade of these receptor signaling pathways significantly reduced mutant KRAS-induced precancerous lesion formation. Together, these data have uncovered a pivotal role for FGFR2 in the early phases of pancreatic tumorigenesis, paving the way for future therapeutic applications of FGFR2 inhibitors for pancreatic cancer interception.

Significance: FGFR2 inhibition reduces mutant KRAS signaling, which can impair mutant KRAS-expressing pancreatic cancer precursor lesions that are prevalent in the average healthy adult and delay pancreatic ductal adenocarcinoma progression.

This article was featured on the cover of the June issue and highlighted in an AACR press release.

Journal: Cancer Research (June 15 issue)

Immunological Tolerance to Luciferase and Fluorescent Proteins Using Tol Mice Enables Development of Improved Tumor Models for Investigating Immunity and Metastasis

There is a continuing need for improved preclinical mouse models of cancer that more accurately predict therapy outcomes for future clinical translation. Luciferase and bioluminescence have long been utilized to generate models conducive to noninvasive imaging to monitor tumor growth, disease progression, and response to therapy. However, luciferase, as well as fluorescent reporter proteins, are highly immunogenic, limiting their use in some syngeneic tumor models in immunocompetent mice. In this study, we described the utility of transgenic mice engineered to have tolerance to luciferase and several other reporter proteins, known as Tol mice, in cancer immunology research. Some tumor cell lines expressing both luciferase and GFP were completely rejected in wild-type mice but maintained robust growth in Tol mice. Additionally, Tol mice allowed the development of an experimental brain metastasis model and a postsurgical resection spontaneous metastasis model. Importantly, even when certain cell lines carrying reporter proteins successfully formed tumors in immunocompetent wild-type mice, underlying immunity existed that could be reinvigorated by immune checkpoint inhibitors. Therefore, caution is needed when using such models in wild-type mice, as exaggerated effects may be induced by immunotherapy. Tol mice circumvent this problem and will likely widen the number of orthotopic and metastatic tumor models that can be used in immunotherapy studies in both C57Bl/6 and BALB/c mice.

Significance: Tol transgenic mice, tolerant to reporter proteins like luciferase and GFP, can be used to develop improved tumor models for studying metastasis and immunotherapy, avoiding immune rejection issues in immunocompetent mice.

A related commentary was published in the June 15 issue.

Journal: Clinical Cancer Research (June 1 issue)

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer

Purpose: Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer are suboptimal, perhaps due to genomic alterations that promote estrogen receptor–independent cyclin D1–CDK4/6 activation. We hypothesized that the addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant would be an effective therapeutic strategy in patients with advanced or recurrent endometrial cancer.

Patients and Methods: In this phase II study, patients with advanced or recurrent endometrial cancer received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included estrogen receptor or progesterone receptor expression ≥1% by IHC, measurable disease, ≤2 prior lines of chemotherapy, and ≤1 prior lines of hormonal therapy. The primary endpoint was the objective response rate by RECIST v1.1.

Results: Twenty-seven patients initiated therapy, and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number–low/no specific molecular profile tumors, 1 response (9%) was in a microsatellite instability–high tumor, and no responses were observed in copy number–high/TP53 abnormal tumors. The objective response rate was 44% (90% confidence interval, 27.0%–62.1%). The median duration of response was 15.6 months. The median progression-free survival was 9.0 months (90% confidence interval, 1.8–20.4). The most common grade ≥3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified.

Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent endometrial cancer; a randomized trial is planned.

A related commentary was published in the June 1 issue.

Journal: Clinical Cancer Research (June 15 issue)

Randomized Phase III Study of EGFR Tyrosine Kinase Inhibitor and Intercalated Platinum-Doublet Chemotherapy for Non–Small Cell Lung Cancer Harboring EGFR Mutation

Purpose: This study was performed to confirm the superiority in overall survival (OS) of EGFR tyrosine kinase inhibitor (TKI gefitinib or osimertinib) monotherapy versus EGFR TKI with intercalation of cisplatin plus pemetrexed as the first-line treatment for patients with advanced non-squamous non–small cell lung cancer (NSqNSCLC) harboring EGFR mutation.

Patients and Methods: This was an open-label, multicenter, randomized phase III study. Patients with chemotherapy-naïve advanced or recurrent NSqNSCLC harboring EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were randomly assigned (1:1) to EGFR-TKI monotherapy or the EGFR TKI plus intercalated chemotherapy group. The primary endpoint was OS, and the secondary endpoints included progression-free survival (PFS).

Results: From December 2015 to October 2020, 501 patients were randomized. The EGFR TKI was changed from gefitinib to osimertinib in October 2018 (gefitinib cohort: n = 308 and osimertinib cohort: n = 193). There was no survival advantage in the EGFR TKI plus intercalated chemotherapy group; the median survival time of both groups was 48.0 months (HR, 0.985; 91.4% confidence interval, 0.796–1.219; one-sided P = 0.4496). The median PFS time was 12.0 months in the EGFR-TKI monotherapy group and 18.0 months in the EGFR TKI plus intercalated chemotherapy group (HR, 0.762; 95% confidence interval, 0.628–0.925; one-sided P = 0.003). The OS and PFS trends in both gefitinib and osimertinib cohorts were identical to those in the entire population.

Conclusions: The intercalation of cisplatin plus pemetrexed after the response to EGFR TKI improved PFS but not OS compared with EGFR TKI monotherapy as the first-line treatment for patients with advanced NSqNSCLC harboring EGFR mutation.

Journal: Molecular Cancer Research

SIRT2 Regulates the SMARCB1 Loss-Driven Differentiation Block in ATRT

An atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive pediatric brain tumor driven by the loss of SMARCB1, which results in epigenetic dysregulation of the genome. SMARCB1 loss affects lineage commitment and differentiation by controlling gene expression. We hypothesized that additional epigenetic factors cooperate with SMARCB1 loss to control cell self-renewal and drive ATRT. We performed an unbiased epigenome-targeted screen to identify genes that cooperate with SMARCB1 and identified SIRT2 as a key regulator. Using in vitro pluripotency assays combined with in vivo single-cell RNA transcriptomics, we examined the impact of SIRT2 on differentiation of ATRT cells. We used a series of orthotopic murine models treated with SIRT2 inhibitors to examine the impact on survival and clinical applicability. We found that ATRT cells are highly dependent on SIRT2 for survival. Genetic or chemical inhibition led to decreased cell self-renewal and induction of differentiation in tumor spheres and in vivo models. We found that SIRT2 inhibition can restore gene expression programs lost because of SMARCB1 loss and reverse the differentiation block in ATRT in vivo. Finally, we showed the in vivo efficacy of a clinically relevant inhibitor demonstrating SIRT2 inhibition as a potential therapeutic strategy. We concluded that SIRT2 is a critical dependency in SMARCB1-deficient ATRT cells and acts by controlling the pluripotency–differentiation switch. Thus, SIRT2 inhibition is a promising therapeutic approach that warrants further investigation and clinical development.

Implications: SIRT2 inhibition is a molecular vulnerability in SMARCB1-deleted tumors.

Journal: Molecular Cancer Therapeutics

Development of a Novel Bifunctional Anti-CD47 Fusion Protein with Improved Efficacy and a Favorable Safety Profile

Therapeutic anti-CD47 monoclonal antibodies (mAbs) are designed to block the CD47–SIRPα checkpoint and promote immune-mediated recognition and elimination of cancer cells. However, current anti-CD47 mAbs have limitations, including off-tumor toxicity and reduced effectiveness in advanced cancers. Additionally, CD47 serves as a death receptor that mediates programmed cancer cell death (PCCD), a mechanism that has not been fully explored in current therapies. In this study, we introduce CO-001, a chimeric bifunctional IgG4 mAb, and its optimized variant CO-005, a bivalent humanized single-chain fragment variable–fragment crystallizable fusion protein. Both CO-001 and CO-005 promoted phagocytosis and PCCD. CO-005, specifically engineered to overcome the safety limitations associated with anti-CD47 antibodies, demonstrates a superior hematologic safety profile in vitro and ex vivo compared with benchmark anti-CD47 antibodies. Notably, CO-005 exhibited no binding to red blood cells, limited binding to white blood cells, and showed no hemagglutination activity. In preclinical models, CO-005 demonstrated potent antitumor activity in B-cell precursor acute lymphoblastic leukemia and Raji lymphoma xenograft models through the dual action of PCCD induction and enhancement of phagocytosis. The ability of CO-005 to trigger strong PCCD while preserving conventional immune responses provides a novel and promising approach for CD47-targeted cancer therapy. Its favorable safety profile, observed in both in vitro and ex vivo studies, positions CO-005 as a promising candidate with potential therapeutic advantages over existing anti-CD47 treatments.

Journal: Cancer Research Communications

Breast Cancer Risk Modification in Women with Pathogenic Variants in BRCA1, BRCA2, ATM, CHEK2, and PALB2

There are limited prospective data on whether established risk factors modify breast cancer risk in women with pathogenic variants (PV) in BRCA1/2 and virtually no risk modification data for ATM, CHEK2, or PALB2. We conducted a nested case–control study in the Women’s Health Initiative (WHI), randomly selecting women with and without breast cancer for DNA sequencing. We evaluated breast cancer odds associated with obesity, family cancer history, smoking, alcohol, parity, breastfeeding, oophorectomy, tubal ligation, neighborhood socioeconomic status, and menopausal hormone therapy (MHT) with estrogen and progestin or estrogen only in PV carriers and noncarriers. In exploratory analyses, we grouped genes by established predisposition for estrogen receptor (ER)-positive (ATM and CHEK2) or ER-negative (BRCA1 and PALB2) disease. Multivariable models with interaction terms were used to assess differential risk modification by PVs. Among 12,957 WHI participants, 287 carried PVs. Breastfeeding was modestly associated with reduced risk for PALB2 [OR = 0.08; 95% confidence interval (CI), 0.00–0.92; P value = 0.042]. With one-sided 95% CI, power was sufficient to exclude OR ≥2.0 with obesity for ATM and BRCA2; smoking and alcohol for CHEK2; no breastfeeding for ATM; no oophorectomy for BRCA2 and CHEK2; no tubal ligation for CHEK2; and neighborhood socioeconomic status for all genes. Estrogen + progestin MHT was modestly associated with increased risk for ER-positive PVs (OR = 7.31; 95% CI, 1.14–64.20; P = 0.036). PVs did not modify risk (interaction P ≥ 0.05). BRCA1/2, ATM, CHEK2, and PALB2 PV carriers do not have breast cancer OR ≥2.0 with many established risk factors. However, MHT warrants additional study in PV carriers.

Significance: There is limited information on whether established risk factors increase breast cancer risk from PVs. In the WHI, PV carriers had no substantial (≥2-fold) increase with most risk factors, except potentially MHT in ATM or CHEK2 carriers. The results may inform counseling and research on MHT.

In 2017, Stuart Sherrow had surgery to remove an aggressive soft tissue sarcoma called dedifferentiated liposarcoma from his abdomen. Three months later, he felt a mass growing in the same spot. His doctors suggested chemotherapy followed by an additional surgery, but they said the cancer would likely keep coming back. “At the time, I didn’t have many options or choices,” Sherrow says. Then his doctors suggested he enroll in a clinical trial investigating whether immunotherapy given before surgery could help shrink the tumor and train his immune system to keep the disease at bay. Sherrow’s cancer responded to the treatment, and he had a second surgery. Today, more than seven years later, Sherrow has no evidence of disease. 

Sherrow’s story illustrates how oncologists are increasingly using immunotherapy before surgery in people with early-stage and locally advanced disease with the goal of improving the body’s long-term ability to fight cancer. “We’ve found that some of these patients who traditionally would be considered incurable appear to be cured,” says Mark Yarchoan, MD, a medical oncologist at the Johns Hopkins Kimmel Cancer Center in Baltimore. The latest issue of Cancer Today, a magazine and online resource for cancer patients, survivors, and caregivers published by the American Association for Cancer Research (AACR), explores the potential benefits of neoadjuvant immunotherapy, as well as questions that remain about the approach. 

Treating Prostate Cancer With PSMA-targeted Therapy  

Another article in Cancer Today’s summer issue details how oncologists incorporate prostate-specific membrane antigen (PSMA)-targeted therapy into care for people with metastatic prostate cancer. While the disease remains incurable, PSMA-targeted therapy is another tool in the oncologist’s toolbox when the prostate cancer stops responding to other treatments. Researchers also are exploring other ways the therapy could be incorporated in care. “There are many, many trials looking at PSMA now,” Praful Ravi, MB, BChir, a medical oncologist at Dana-Farber Cancer Institute in Boston, tells Cancer Today. “They’re looking at targeted agents all across the disease spectrum and not just in the advanced setting.” 

Overcoming Shame, Finding Support, and More Advice for Cancer Patients 

In the same issue, Cancer Today explores how people with cancer often feel shame about their diagnosis—whether because it is an “embarrassing” type of cancer or they feel they’re responsible for their disease. Researchers have found that people who feel shame about their cancer may delay medical care or withhold details from their oncologist. As researchers become more aware of how shame can be detrimental to cancer care, they are developing ways to help patients overcome those negative feelings. 

Additionally, Cancer Today highlights Lorrinda Gray-Davis, a liver cancer survivor who received a liver transplant in 2018. Since her surgery, Gray-Davis has hosted support groups that create a community for transplant recipients—something she wishes she’d had during treatment. “That was the worst part of my journey—that lack of knowing anyone who knew what I was going through,” she says. 

Cancer Today’s latest issue also provides practical information for patients, including analysis of the recent approval of a T-cell receptor therapy for synovial sarcoma. Articles also offer advice on topics ranging from how to prevent treatment-related bone damage to dealing with cancer ghosting. Plus, William G. Nelson, MD, PhD, director of the Johns Hopkins Kimmel Cancer Center and Cancer Today’s editor-in-chief, provides commentary about the link between air pollution and lung cancer risk. 

The AACR offers Cancer Today free of charge to those affected by cancer. To view content from the summer issue, visit Cancer Today’s website or read the digital edition.  

To stay up to date with the latest in cancer research and care, subscribe to the magazine or sign up to receive Cancer Today’s e-newsletter released twice a month. 

Ten years ago, the American Association for Cancer Research (AACR) launched Project GENIE (Genomics Evidence Neoplasia Information Exchange) with the goal of providing cancer researchers with access to real-world, clinico-genomic data from multiple institutions that they couldn’t find in any one place—the type of data necessary to fulfill many researchers’ wishes of being able to study rare genetic variants.  

“Our initial founding principle was the idea that we had to combine data because no single institution would’ve had enough information on rare variants or rare cancers to really make a meaningful impact using just their own data,” said Shawn M. Sweeney, PhD, senior director of the AACR Project GENIE Coordinating Center. 

By January 2017, eight institutions had contributed to this new publicly accessible data registry. Today, 20 institutions worldwide have contributed more than 200,000 total samples to AACR Project GENIE, with new releases of additional sequencing data announced every six months. 

“I don’t think there is any other dataset that’s collected as many genomic sequenced samples as AACR Project GENIE has,” said Kenneth L. Kehl, MD, MPH, from Dana-Farber Cancer Institute, the current chair of AACR Project GENIE. “And that enables a number of different types of analyses that wouldn’t otherwise be possible.” 

At the AACR Annual Meeting 2025, held April 25-30, such possibilities were on full display. Researchers showcased using AACR Project GENIE data in a number of different ways, including to identify potential therapeutic opportunities for a rare cancer, test out an artificial intelligence (AI) platform that provides insights on colorectal cancer, develop a new targeted tumor-agnostic therapy, and understand the differences between early-onset and late-onset gastroesophageal cancers. 

A Deeper Understanding of a Rare Kidney Cancer 

While targeted therapies and immunotherapies have shown promise for common forms of kidney cancer, options are much more limited for patients with a rare and aggressive kidney cancer subtype called collecting duct carcinoma (CDC). 

A deeper understanding of the molecular underpinnings of CDC is needed to identify new therapeutic opportunities, said Xiaofan Lu, PhD, of the University of Strasbourg.  

“There is limited data published for rare cancers,” said Lu. “But we found that there’s a lot of data about rare cancers in the [AACR Project GENIE] database, which was very useful for our study to validate the findings.” 

In the study he presented, Lu performed whole exome sequencing, RNA sequencing, and DNA methylation profiling to characterize the gene mutation and expression patterns of 22 cases of CDC. He then validated the findings against 25 CDC samples housed in the AACR Project GENIE database. 

Lu’s analyses revealed that mutations in the NF2, LZTR1, and SMARB1 genes, found on chromosome 22q, were common in CDC and that copy number loss of chromosome 22q occurred in more than half of the cases examined. In addition, Hippo signaling was frequently dysregulated due to mutations in the NF2, SAV1, and WWC1 genes, leading to overexpression of the YAP gene signature. Further, CDC was found to have upregulation of cell cycle and immune cell enrichment signatures that were not found in other kidney cancer subtypes.  

Lu also examined the tumor microenvironments of CDC, finding that immunologically “hot” tumor microenvironments were enriched for CD8 T cells, B cells, tertiary lymphoid structure signatures, and mutations in DNA damage response genes. Conversely, immunologically “cold” tumors frequently had copy number loss of chromosome 22q and overexpression of the YAP gene signature.  

He also demonstrated that the loss of chromosome 22q and mutations in DNA damage response genes were effective biomarkers to predict tumor response to immune checkpoint inhibition. 

“We added to the knowledge of pathogenesis of this disease, including, for example, chromosome 22q loss … which was never reported before,” said Lu. “We also identified … a subset of [CDC] that might respond to immune checkpoint inhibitors. We think our study would be beneficial to those patients diagnosed with this challenging disease.” 

Validating a Conversational AI System  

Enrique Velazquez-Villarreal, MD, PhD, MPH, of City of Hope, had a wish: a conversational AI platform that researchers could use to query datasets with simple natural language to help in their quests to advance precision medicine. But using publicly available platforms resulted in issues, including hallucinations. One example he provided: asking about the TAILORx clinical trial and getting a citation about Taylor Swift. So, Velazquez-Villarreal and his team built a new platform from scratch.  

Called the Precision Medicine AI Agent (PM-AI), their model turns clinical, social determinants of health, and genomic data into tokens that can be more easily analyzed using AI. Users can then conduct integrative data analysis by querying with pertinent questions, such as potential molecular biomarkers, how patients from different socioeconomic backgrounds or ethnic groups react to different therapeutics, or treatment strategies for patients with different KRAS mutations. The program can supply analysis within hours, compared to the weeks or months it can take to get a similar analysis using other platforms.  

To validate the platform, Velazquez-Villarreal’s team conducted a case-control study using data from The Cancer Genome Atlas (TCGA), cBioPortal for Cancer Genomics, and AACR Project GENIE. PM-AI was asked to compare how patients with colorectal cancer respond to FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) depending on whether they have RAS mutations. The platform identified KRAS as a predictor of poorer response and increased risk of recurrence, which is consistent with published findings.  

Velazquez-Villarreal said that in addition to publicly available data sources, researchers can also use PM-AI to query their own data. 

“We want to help researchers take advantage of this AI revolution,” Velazquez-Villarreal explained. “By using the AACR Project GENIE dataset, we are able to provide researchers with an opportunity to interact with this AI agent for the first time and feel confident about how the technology works before they work to adopt or improve upon this open-source model for their own purposes.” 

Reigning in a Rogue Genome Guardian 

As the guardian of the genome, the p53 tumor suppressor pathway is one of the body’s most important defenses against cancer. When cells are damaged, p53 springs into action to help them fix themselves or, if the damage is too severe, to trigger them to self-destruct. But when p53 itself mutates, cells lose their brakes and threaten runaway malignancy. One such variation results from the R175H missense mutation that changes the shape and function of the p53 protein. 

With the aid of AACR Project GENIE, a team at Clasp Therapeutics led by Kristen McEachern, PhD, analyzed genomic data from over 180,000 tumor samples to determine the frequency of this mutation that cripples p53’s protective power. Overall, R175H mutation occurred in about 2% of all tumors and more often in tough-to-treat diseases like colorectal, pancreatic, and ovarian cancer. This allowed them to estimate how many patients might benefit from new targeted therapies like CLSP-1025, thus defining an addressable population 

CLSP-1025 is a bispecific T-cell engager designed to direct immune assassins to cancer cells that possess this altered version of p53.  

One end of the diabody drug recognizes a peptide fragment unique to the R175H mutant, so long as it is presented in the context of a complex called HLA-A*02:01, which about 41% of people in the United States carry, according to the researchers. The other end of CLSP-1025 binds and activates T cells, triggering their cancer-killing function. 

Going after any form of mutant p53 has been hard because the full protein is expressed only inside of cells. But by using an antibody that connects the immune cells to cancer cells that express the mutant p53-HLA combo on their surface, this treatment turns this previously “undruggable” protein into a precision immunotherapy target. Thus far, the approach has shown promise preclinically, and the investigators have launched GUARDIAN-101, the first-in-human trial of CLSP-1025, earlier this year in patients with solid cancers. 

McEachern explained that the GENIE database “helped us to define a clear patient population for our ongoing phase I trial and support a tumor agnostic approach so that we can bring this important therapy to as many patients as possible.” 

Understanding the Molecular Landscape of Early-onset Cancers 

With cancer becoming increasingly common in younger populations, identifying the factors underlying early-onset cancers will be critical to developing successful prevention and therapeutic strategies. 

To this end, Ronan McLaughlin, MBBCh, BAO, of Princess Margaret Cancer Centre, used data from AACR Project GENIE to understand how molecular and clinical features differ between early-onset and late-onset gastroesophageal cancers (GEC). He examined data from 5,897 patients, 943 (16%) of whom had been diagnosed with GEC at age 50 or younger. 

The analysis benefited from data collected across 17 different institutions, McLaughlin noted, and it identified 26 genes that were differentially mutated between early-onset and late-onset GEC. All but two of these genes were more frequently mutated in late-onset GEC and included potentially actionable mutations, such as those in the CDKN2A, KRAS, FGF4, and FGFR3 genes. 

The genes CDH1 and CCNE1 were significantly more likely to be mutated in early-onset GEC than in late-onset cases. McLaughlin noted that CDH1 and CCNE1 mutations were previously found to be associated with hereditary gastric cancer syndromes, aggressive disease, and poor survival.  

Compared with the late-onset GEC cohort, the early-onset cohort had a higher proportion of female patients and a higher percentage of Asian patients. Survival analyses did not reveal statistically significant differences between the cohorts; however, patients with early-onset GEC had numerically shorter progression-free survival. 

“Looking at somatic mutations has allowed us to identify two mutations that are identified more commonly and enriched in that younger-onset group,” McLaughlin said. “[The findings] will allow us to develop targeted therapies, design future clinical trials, and ultimately [impact] patient outcomes.” 

While most individuals, including cancer patients, understand that exercise is good for overall health, several recent studies have highlighted just how much of an impact physical activity can have on survival and quality of life for patients with cancer.  

Associations between exercise and benefits to cancer patients have long been studied. A recent publication found that more than 3,000 papers have examined such associations, with many indicating that exercise can help improve anxiety, depression, fatigue, and physical functioning, among other factors. Studies have also shown that physical activity can help lower the recurrence of cancers, improve overall quality of life, and even increase survival, as outlined in the AACR Cancer Progress Report 2024.

But how much exercise should cancer survivors be doing? How soon should they start exercising following their diagnosis? What types of exercise can lead to various improvements in their quality of life? Recently published studies have explored these questions and provided further evidence into the benefits of physical activity for cancer patients.    

When Should Cancer Patients Start Exercising? 

Researchers at the National Cancer Center of the Republic of Korea conducted a population-based retrospective study of the impact of physical activity immediately after cancer diagnosis. They evaluated sufficient physical activity, defined as vigorous physical activity (e.g., running, aerobics, climbing) for 75 to 150 minutes per week or light/moderate physical activity (e.g., walking, doubles tennis, bike riding) for 150 to 300 minutes per week.  

The data, published in the AACR journal Cancer Epidemiology, Biomarkers & Prevention, found that of the 215,191 participants, those who maintained sufficient physical activity following their diagnosis had a lower risk of death from any cause compared to those who remained inactive. For men, the risk of all-cause mortality dropped between 18% to 23% across all cancer stages, while for women, the risk dropped between 13% to 19% but only when they were diagnosed at an early stage. The reduction in risk varied based on the cancer type, cancer stage, and level of physical activity. In terms of death specifically from cancer, the risk significantly reduced for men with gastric, colorectal, liver, and lung cancers, and for women with colorectal cancer.       

In another study, also published in Cancer Epidemiology, Biomarkers & Prevention, researchers from the National Institutes of Health and other institutions specifically looked at the benefit of post-diagnosis physical activity for patients with breast cancer. They wanted to understand the impact on those who meet the standard recommended guidelines of at least 150 minutes per week of aerobic exercise and at least two days per week of muscle-strengthening exercise.  

Based on data from 50,689 female breast cancer patients that they collected from 20 previously conducted studies, they found that compared to those who did no or minimal exercise, the unadjusted all-cause mortality dropped by 8% in those who followed the recommended guidelines. 

Can Exercise Reduce the Risk of Cancer Recurrence? 

Previous observational studies have found that exercise could help lower the risk of recurrence for patients with colorectal cancer, but researchers with the Canadian Cancer Trials Group tested this in a phase III clinical trial. From 2009 through 2024, the CO.21 Colon Health and Lifelong Exercise Change (CHALLENGE) trial enrolled 889 patients who had complete resection of stage 3 or high-risk stage 2 adenocarcinoma of the colon and completed adjuvant chemotherapy. Patients were randomly assigned to either receive education about the benefits of diet and exercise (444) or to receive that information while also participating in a supervised three-year exercise program (445).  

As part of the exercise program, patients attended mandatory, behavioral-support sessions designed to help each individual overcome any barriers that may prevent them from exercising, such as long-term side effects from treatment or finding a place and time to exercise.  

The goal was to help participants increase their recreational aerobic exercise from their own individual baselines by at least 10 metabolic equivalent task (MET)-hours per week in the first 12 weeks and then maintain that level or continue to increase it over the course of the rest of the program. Each participant could select the type of exercise they were most comfortable with. For example, brisk walking for an hour is equal to about 4 MET-hours while an hour of jogging is about 10 MET-hours.  

At a median follow-up of 7.9 years, exercise was found to reduce risk of recurrence, a new primary cancer developing, or death by 28%. Additionally, disease-free survival was significantly longer in the exercise group compared to the health-education group after both five years (80.3% vs. 73.9%) and eight years (90.3% vs. 83.2%), according to the results published in the New England Journal of Medicine.  

Can Exercise Help Improve Sexual Functioning for Cancer Survivors? 

Male prostate cancer survivors may experience side effects impacting their sexual function that may last for up to 15 years following treatment. In a study published in JAMA Network Open, researchers at Peter MacCallum Cancer Centre and other Australian institutions conducted a three-arm clinical trial to see if exercise and psychosexual education could improve erectile function. Participants were randomly assigned either to a six-month supervised resistance and aerobic exercise program, the same program plus psychosexual education and self-management intervention, or standard medical care.  

The exercise program included 20 to 30 minutes of cardiovascular exercises on a treadmill, cycling or rowing ergometer, or elliptical or cross trainer, three days per week. Participants were also asked to exercise on their own so they could reach 150 minutes of moderate-intensity aerobic exercise per week. The resistance training included six to eight exercises targeting both upper and lower body muscle groups with repetitions ranging from six to 12 and sets from one to four per exercise.  

Sexual function was assessed using the International Index of Erectile Function (IIEF), and after six months, the adjusted mean difference in IIEF scores increased by 5.1 points in the exercise group compared to 1 point in the standard-of-care group. The effects of exercise on sexual function were greater for those who had received radiotherapy (4.2-point increase) or androgen deprivation therapy (4.4-point increase) compared to prostatectomy (1.6-point increase). The addition of psychosexual education and self-management intervention did not show a significant benefit. 

In another study, exercise was also found to improve sexual functioning for women with metastatic breast cancer who experience symptoms following treatment that impact sex. Results of the PREFERABLE-EFFECT study, published in the International Journal of Cancer, revealed that compared to those who received usual care, patients who participated in an exercise program for six months reported an average 5.6-point increase on a questionnaire evaluating their sexual functioning. 

The exercise program included supervised one-hour exercise sessions twice a week that involved resistance, aerobics, and balance training. Women in the exercise arm also reported an average 7.1-point decrease in vaginal symptoms associated with their cancer or treatment compared to the standard-of-care arm. 

What Are the Quality of Life Benefits From Exercise? 

Researchers at Shengjing Hospital and other institutions in China recognized that studies about exercise in relation to cancer have found contradictory results. So, they performed an umbrella review, published in the British Journal of Sports Medicine, which ultimately examined 80 randomized controlled trials to evaluate the reliability of the associations found between some form of exercise and a resulting benefit for cancer patients. Out of 485 associations mentioned, they determined that 260 were statistically significant with moderate-level evidence and 81 were supported by high-certainty evidence.      

For example, yoga was among the exercises that had at least moderate-level evidence in helping women with breast cancer alleviate gastrointestinal symptoms caused by their treatment, reduce short-term sleep disturbances, improve short-term quality of life, enhance social well-being, and decrease depression when combined with exercise. The study also found that evidence supported qigong and tai chi in relieving anxiety in patients with various cancer types, high-intensity interval training in reducing cancer-related pain, and mind-body exercise in improving cognitive function in lung cancer patients. 

Looking at exercise in general, the study found physical activity helped to alleviate the symptoms of chemotherapy-induced peripheral neuropathy, improve dyspnea in people with advanced-stage cancer, reduce the risk of pulmonary complications following surgery in patients with non-small cell lung cancer, as well as boost the psychological well-being and overall quality of life of older patients with colorectal cancer. But those were just some of the many benefits found that should have cancer patients considering ways they can stay physically active.  

The AACR Annual Meeting 2025, held April 25-30, featured six Plenary Sessions that explored exciting areas of cancer research, including cancer evolution; KRAS, extrachromosomal DNA (ecDNA), and cancer vaccines; innovative technology advancing organoid models, cellular therapeutics, liquid biopsy, and clinical trials; targeting the tumor ecosystem; predictive oncology; and a wrap-up of the meeting’s main themes. If you missed any of the talks, or just want a quick refresher, here is an overview of each session.

What Factors Are Driving Cancer Evolution?

The speakers of the Discovery Science Plenary took attendees on a journey that examined “Novel Mechanisms Influencing Cancer Evolution,” including somatic mosaicism, metabolism, epigenetic alterations, and the microbiome.

Inigo Martincorena, PhD, of Wellcome Sanger Institute, kicked the presentations off with a glimpse into the “hidden world of somatic evolution.” Along the way, he discussed how factors such as alcohol and smoking influence the emergence of mutations, how these mutations can contribute to the phenomena of somatic mosaicism and tumor heterogeneity, and how genomic alterations like copy number variants are much less common.

The next stop on the journey examined metabolic vulnerabilities in kidney cancer that might be applicable to other types of tumors. M. Celeste Simon, PhD, FAACR, of the University of Pennsylvania Perelman School of Medicine, explained how the high-density lipoprotein (HDL) receptor SCARB1 can disrupt ferroptosis and that inhibiting SCARB1 might mitigate a tumor’s malignant features and help to augment treatments like immunotherapy.

Next up, Yang Shi, PhD, FAACR, of the Ludwig Institute for Cancer Research, shared strategies for manipulating cancer cell signaling via epigenetic alterations. He explained his team’s efforts to inhibit LSD1 and GSK3 to force leukemia cells to differentiate and mature, thereby neutralizing their aggressive growth and potentially providing an effective treatment strategy.

Finally, Nicola Segata, PhD, of the University of Trento, explored ways to use the microbiome to improve the diagnosis and treatment of cancer, such as through fecal microbiota transplant (FMT). He pointed to insights gained from the TACITO and FMT-LUMINate clinical trials regarding how FMT can help overcome resistance to immunotherapy.

“The next point will be to understand why [FMT] works and how it works because if we are able to understand which of the features are key, then we can think about next-generation biotherapeutic approaches,” Segata said.

Advances in KRAS, ecDNA, Cancer Vaccines, and the Tumor Microenvironment

The Opening Plenary, “Unifying Cancer Science and Medicine—A Continuum of Innovation for Impact,” reflected the meeting’s theme of carrying scientific discoveries through to meaningful clinical impact, with each presentation touching on the clinical implications of laboratory findings. The session focused on four areas of science, starting with a presentation by Kevan M. Shokat, PhD, FAACR, of the University of California, San Francisco, on new approaches to target KRAS-mutated cancers. Shokat, who developed the first inhibitor approved by the U.S. Food and Drug Administration for this once-considered undruggable oncoprotein, discussed a new lead compound for KRAS G12D as well as the promise of active RAS-ON inhibitors and protein degraders under investigation.  

Then, Paul S. Mischel, MD, FAACR, of Stanford University, examined the tumor-promoting roles of ecDNA, starting his presentation with an overexposed microscopy image that revealed the ecDNA “hiding in the nucleus, in plain sight, wreaking havoc.” He went on to show how collisions between transcription and replication machinery on ecDNA activate the DNA damage protein CHK1, which makes CHK1 inhibition a potential approach for treatment.

“We’ve come a long way in understanding the importance of [ecDNA],” Mischel said. “It’s very prevalent, and it’s very devastating.”

Johanna A. Joyce, PhD, FAACR, of Ludwig Institute for Cancer Research, focused on the interactions between cancer cells and immune cells within the tumor microenvironment (TME) and her use of animal models and spatial technologies to examine the impact of treatment on the brain TME.

“What was really quite striking is the emergence of fibrotic scars following radiation, and where the glioma recurs is precisely where that scar had formed,” said Joyce. “By blocking the formation of fibrotic scars, we can directly impact tumor recurrence.”

Catherine J. Wu, MD, FAACR, of Dana-Farber Cancer Institute, concluded the session with a look at the potential of cancer vaccines to treat various cancer types, including ovarian cancer. Wu reported that an investigational neoantigen-targeted vaccine led to stable disease in three of 10 patients with advanced ovarian cancer and induced a neoantigen-specific immune response. In contrast, tumors that progressed after vaccination exhibited signs of immune evasion.

“We are seeing a multitude of immune-evasive mechanisms at the time of progression,” she explained. “We need to identify those events earlier on, and, certainly, understanding this will inform us on how to devise more rational approaches to address advanced disease.”

Innovative Technologies in Cancer Research

Have you ever heard of a “minicolon” model? If you read our From the Bench series, you may have, and if not then the third Plenary Session of the AACR Annual Meeting 2025 provided a second chance to learn about this creative creation and other “Innovative Technologies Driving Advances in Cancer Research.” Matthias P. Lütolf, PhD, of the Roche Institute of Human Biology, showed off these organoids shaped to mimic intestinal crypts, which can be used for tracing cell lineages and performing drug screens.

“We think that such models will finally start to allow us to capture some of the complexity of processes that can only be modeled in an animal,” Lütolf said.

Marcela V. Maus, MD, PhD, of Mass General Hospital, said she believes the “power behind cellular therapeutics is really the potential for innovation.” Along with her colleagues, she is working on knocking out the interferon gamma receptor in chimeric antigen receptor (CAR) T cells to enhance the cells’ efficacy.  She also promoted the use of CRISPR knockout screening to identify other modifications that can further optimize CAR T cells.

Trevor Pugh, PhD, of the Ontario Institute for Cancer Research, then explored some innovative uses of liquid biopsy. These included how fragmentomics is enhancing the accuracy of early detection for some cancer types and how liquid biopsy is helping to reconstruct the genomes of primary tumors that have been significantly damaged by therapy.

Muhammad Shaalan Beg, MD, MBA, of the National Cancer Institute, then advocated for the use of innovative technology in clinical trials. He pointed to how telehealth, remote monitoring, and mobile nursing are already allowing more patients to participate in clinical trials.

“We need to urgently deploy these methods, redefine what’s feasible … and how we can innovate on these in a way that improves clinical trial access and helps us speed up the development of cancer treatments,” Beg concluded.

Finding Connections Within the Cancer Ecosystem

The “Targeting the Cancer Ecosystem” Plenary Session, discussed the study of how normal stromal cells that coevolve with cancer cells have an impact on cancer’s growth and response to treatment.

For example, Yardena Samuels, PhD, of the Weizmann Institute of Science, is exploring how different forms of tumor heterogeneity can influence antitumor immune responses. Her team identified how the secreted migration inhibitory factor (MIF) appears to promote immunosuppression, even when its expression is limited to half of the clones. By identifying such links between intratumoral heterogeneity and targetable antigens, Samuels said it could be possible to then devise methods that account for this heterogeneity to reengineer the immunosuppressive tumor microenvironment. 

“We have seen many successes in the immunotherapy field, [but] we still have a big gap in treating tumors with immunotherapy, and especially tumors of high heterogeneity,” she explained. 

Meanwhile, Matthew F. Krummel, PhD, of the University of California, San Francisco, explained the importance of defining “archetypes,” which he described as collections of cells that are linked across tissue types and that the immune system uses to complete its various functions. Discovering dominant immune archetypes reflected in tumor biology, Krummel said, could allow doctors to better tailor therapeutic approaches to fit individual patients based on the archetypes present in their tumors. In parallel, his team is also working to develop “nudge” drugs that could coax suboptimal immune archetypes within tumors toward more desirable states.   

Kurt A. Schalper, MD, PhD, of Yale University, discussed his work examining the spatial relationships between tumor and immune cells. For instance, by using his team’s three-dimensional analytical method they found that as lung tumors metastasize, they evade immunity more effectively and change the structure of their microenvironment. As a result, tumors with high baseline spatial heterogeneity were less responsive to immunotherapy, both alone and in combination with PARP inhibition. But, he explained, this “can actually be mediated by these molecules we call T cell excluders, that have high diagnostic and therapeutic potential.”

Mariam Jamal-Hanjani, MD, PhD, of University College London, is also studying the changes that occur during lung metastasis. In longitudinal studies of patients with lung cancer, her team found that tumors often have multiple clones with metastatic capacity, and that metastases-to-metastases seeding is common. However, clones differ based on where they establish themselves, which can lead to a divergence between the tumor microenvironments in primary and metastatic tumor sites—yet another layer of heterogeneity that researchers must consider.

Predictive Oncology: Treatment Response, Tumor Trajectory, and More

In the plenary on “Opportunities in Predictive Oncology,” speakers examined the advances in multiomic and multiscale technologies that may help achieve the ultimate goal of predicting responses to treatment at the individual patient level.

For instance, recent research has shed light on the novel concept of an “oncotecture” within each cell. As Andrea Califano, Dr, FAACR, of Columbia University, explained, this integrated cancer architecture keeps a pulse on all of the information that dictates the state of a tumor cell. He said that in the research setting they can use algorithms in conjunction with patient data to help predict which combinations of therapies would be effective against a tumor’s specific cell state.  

“We don’t have to come up with personalized medicine recipes that are unique to the individual,” Califano explained. “We have to come up with personalized recipes that are unique to the actual cell state.”

Christina Curtis, PhD, MSc, of Stanford University, discussed efforts to use “digital twins” to help predict a tumor’s future trajectory, treatment resistance, or disease relapse. These digital models replicate the dynamic behavior of life—at the molecular, cellular, and tissue levels—and are allowing Curtis and others to collect new insights about cancer, including in breast cancer where her team was able to uncover novel vulnerabilities to target.

“With these tools in hand, we can not only develop improved biomarkers, we can better risk stratify,” she explained. “We might be able to intercept, and this should certainly inform the approach to therapeutic development.”

To better understand treatment resistance, Marleen Kok, MD, PhD, of the Netherlands Cancer Institute, has studied what differentiates long-term from short-term responders in immunotherapy-treated patients with triple-negative breast cancer (TNBC). Her group found that spikes in both tumor-targeting T cells and immune checkpoint expression after patients started immunotherapy were predictive signs of durable benefit to therapy. However, the majority of responding TNBC tumors eventually developed secondary resistance.

“At baseline, those patients have a more favorable tumor microenvironment, but if you look further, you see that secondary resistance is related to loss of B cells, loss of clonal T cells, and downregulation of the antigen presentation machinery.”

Trey Ideker, PhD, of UC San Diego, wrapped up the session by looking at the potential for artificial intelligence to improve decision-making in the clinic. He showcased deep-learning systems embedded with structural tumor cell maps that shed light on novel, highly penetrant drug-mutation interactions involving members of the PARP family of DNA repair molecules.

Highlights From Across the Meeting

The closing Plenary Session put this year’s AACR Annual Meeting into perspective by summarizing the core themes that emerged and some of the long-term implications of what was discussed.

“I have been attending the AACR [Annual] Meeting for 30 years, and I’ve really seen the evolution in what’s [been] happening over the years,” said Cory Abate-Shen, PhD, of Columbia University, who spoke about the basic and translational discoveries reported at the meeting. “The perspective I took was to think about what has been changing in the 30 years since I’ve been attending—and it’s a lot.”

That includes some of the work presented in the other Plenary Sessions, with Abate-Shen noting the seminal work of Shokat that is paving the way for new approaches to target RAS; the advances in our understanding of ecDNA, as discussed by Mischel and others at the meeting; the progression of predictive oncology; new revelations about fibrosis, metastasis, and more thanks to a deeper dive into the tumor ecosystem; the research into the microbiome that is leading to new ways to detect cancer and monitor treatment; and new insights into aging-related changes associated with cancer, including what Martincorena shared about somatic evolution.

Beyond the Plenary Sessions, Abate-Shen was also excited about the identification of several new targets such as the Hippo pathway, epigenetic regulators, and specific compartments of cancer cells like nuclear speckles. She also mentioned the future implications of targeting lineage plasticity to counter drug resistance, growing our understanding of the neuroscience of cancer and the nerve-cancer crosstalk, and what research into the sex differences of non-hormone regulated cancers could reveal.   

Scarlett Lin Gomez, PhD, MPH, of the University of California, San Francisco, was tasked with providing an overview of the significant findings in prevention, early detection, population sciences, and disparities research. The impact of lifestyle and societal factors on cancer risk were among the major topics with presentations on the ability of GLP-1 to protect against cancer and how chemotherapy is associated with subsequent cancers in pediatric patients. The meeting also provided insights into early-onset cancer, including the populations that are most impacted, potential risk factors, and the influence of the microbiome.

In terms of cancer screening and prevention, she highlighted groundbreaking clinical trial results showing that one dose of the HPV vaccine was no less effective than two doses in preventing infection as well as studies on mailing fecal immunochemical tests and self-collection of cervical samples to improve screening rates for colorectal and cervical cancer, respectively.

Jayesh Desai, MBBS, of Peter MacCallum Cancer Centre, finished off the session with the major takeaways from the clinical trials program. He noted how PD-1 blockade with dostarlimab (Jemperli) helped some patients with locally advanced, mismatch repair-deficient cancers (dMMR) avoid surgery; the improved outcomes for head and neck cancer with the addition of pembrolizumab (Keytruda) to standard of care before and after surgery; the use of circulating tumor DNA to detect relapse and guide treatment for patients with early-stage dMMR solid cancers; the promise seen in new therapeutic targets like the Werner helicase; and how targeting ICAM-1 is advancing the use of T-cell therapies for solid tumors.

“Cancer drug development is really at an exciting time,” Desai concluded.

In this edition of From the Bench, researchers take bold steps to reimagine what cancer treatment and detection could look like. What if you could trick the immune system into seeing tumors as pig organs so they are rejected? Or design a synthetic receptor with remote control settings? One team even asked: Could fat cells—yes, fat cells—starve tumors into submission? 

This season’s roundup also includes a cleverly named blood test for pancreatic cancer that may help catch the disease in its earliest stages, as well as a large-scale study that pieces together how prostate tumors evolve, with an eye toward more precise early diagnostic strategies. 

Together, these inventive approaches highlight the creativity and cross-disciplinary thinking fueling today’s cancer research and hint at where the field is headed next. 

Unleashing Circe: Turning Tumors Pig-like to Trigger Antitumor Immunity in Patients

In Homer’s “Odyssey,” the sorceress Circe famously turned Odysseus’ crew into pigs. In a new study, cancer researchers are taking a similar approach to combat cancer—making tumors pig-like.

Organ rejection is a common issue facing transplant recipients, particularly when patients receive organs from pigs. This occurs because a patient’s immune system recognizes the transplanted organ as foreign and mounts an attack against it. In an article published in Cell, researchers from Guangxi Medical University and other institutions in China reported how they could exploit the mechanisms underlying pig organ rejection to devise a new strategy to fight tumors.

The researchers designed an oncolytic virus that expresses alpha 1,3-galactotransferase (α 1,3-GT), which is the protein in pig organs that triggers the human immune system to attack the organs after transplantation. Since the oncolytic virus preferentially replicates in cancer cells, the approach ensures that α 1,3-GT is expressed primarily by cancer cells and that the subsequent immune response is targeted to cancers and not healthy tissue—in essence, making human tumors resemble pig organs so that the immune system attacks them.

The strategy was effective in cynomolgus monkeys with liver cancer, inducing an immune response and extending survival by several months. In a clinical trial, the oncolytic virus led to disease control in 18 of 20 patients with treatment-refractory cancers, including one complete response and six partial responses. The authors suggest that these preliminary results support the strategy’s efficacy and potential for clinical translation.

Back to the ’90s: Transmitting Messages Through PAGERs

It’s 2025, but a new study out of Stanford University, published in Nature, suggests that PAGERs might still be relevant. In this case, researchers are referring to a new cell signaling system they developed, which they call “programmable antigen-gated G-protein-coupled engineered receptors” (PAGERs).

PAGERs are synthetic receptors designed to activate a signaling pathway of choice upon binding to an extracellular target antigen. Like prior synthetic receptor approaches, PAGERs allow researchers to reprogram cell behavior for cancer research and treatment. Unlike prior synthetic receptor approaches, however, PAGERs can pair with mobile antigens (no pun intended!) and have built-in drug control.

The PAGER design includes an autoinhibitory nanobody domain that binds to the receptor and keeps it “off” unless the target antigen is present. In the presence of the target antigen, the autoinhibitory domain releases from the receptor in order to bind to the antigen, and the receptor becomes available to bind to an activating drug, which triggers activation of downstream signaling. This two-step system ensures that downstream signaling is activated only when the target antigen and activating drug are both present.

The researchers demonstrated potential applications of the system, such as promoting T-cell migration in response to a soluble antigen, controlling when macrophages differentiate, and secreting antitumor antibodies upon detection of a tumor antigen.

Hungry, Hungry Lipo(cytes): Outcompeting Cancers for Essential Nutrients

Cancers are characterized by a voracious “appetite”—a heightened ability to consume and metabolize nutrients to fuel their growth. But what if you surround cancer cells with cells with an even bigger appetite?

In a recent study published in Nature Biotechnology, researchers from the University of California San Francisco and other institutions demonstrated that they could essentially starve cancers by transplanting fat cells (also called “lipocytes” or “adipocytes”) that are engineered to outcompete cancer cells for essential nutrients.

The fat cells were engineered to have higher-than-normal expression of the UCP1, PRDM16, or PPARGC1A genes, which led to increased glucose and fat metabolism. When these engineered fat cells were cocultured with cancer cell lines, the cancer cells exhibited significantly reduced proliferation and decreased glucose uptake and metabolism. Similarly, transplanting the engineered fat cells into mice reduced tumor size and suppressed cancer progression. The authors propose their strategy as a potential therapeutic approach for a variety of cancer types.

One Stop Washout: A Three (target)-in-One CAR T-cell Conditioner for Leukemia 

Acute myeloid leukemia (AML) is a deadly disease that’s difficult to treat and even harder to keep in remission, especially in children. Standard therapy involves aggressive chemotherapy to clear out the diseased bone marrow, followed by a stem cell transplant to provide healthy new hematopoietic stem cells. But this approach comes with harsh, often serious side effects. Worse, some leukemias come roaring back even after this grueling process, fueled by stubborn leukemia stem cells that resist standard treatment. 

As highlighted in a study published in Molecular Therapy: Oncology, scientists from the Stanford University School of Medicine and University of Wisconsin-Madison have engineered a new kind of CAR T-cell therapy, cleverly dubbed “ELECTRIC CARs,” to address these exact problems. These genetically modified immune cells are designed to recognize and attack three targets—KIT, FLT3, and MPL—all at once. Importantly, these targets are expressed by both normal blood cells and leukemia cells within the bone marrow, so the CAR T cells eliminate cancer cells while also clearing out the microenvironment. This helps prep the bone marrow for a new stem cell transplant, without the need for traditional chemotherapy. 

In lab tests and mouse xenograft models, ELECTRIC CARs showed impressive potency against AML. If proven safe and effective in humans, these novel CAR T cells could radically transform AML care, offering a less toxic way to fight a notoriously tough cancer while setting the stage for lasting recovery. 

PAC-MANN: A Game-Changer in Pancreatic Cancer Detection 

Pancreatic cancer is notoriously difficult to detect early, often leading to poor survival rates. While CA 19-9 represents the gold standard blood-based biomarker for pancreatic cancer, it does not catch all cases, so incorporating other molecules linked to disease could enable earlier detection and hopefully better outcomes for patients. 

To that end, a team from Oregon Health & Science University and Stanford University School of Medicine developed PAC-MANN, a new blood test that uses a tiny blood sample to detect the activity of enzymes that remodel the pancreatic tumor environment, and published their work in Science Translational Medicine. PAC-MANN could distinguish between pancreatic ductal adenocarcinoma (PDAC) and healthy tissue as well as noncancerous pancreatic disease. Furthermore, combining PAC-MANN with CA 19-9 analysis enabled the detection of stage 1 PDAC with high sensitivity and specificity. Beyond detection, PAC-MANN may also help monitor treatment effectiveness by tracking changes in protease activity over time, as one study showed. 

As this technology is refined and validated, PAC-MANN could become a powerful tool that enables earlier detection of pancreatic cancer, with a simple blood draw, and provide doctors a better opportunity to cure patients. For a disease that often hides until it’s too late, this could help flip the script and bring pancreatic cancer out of the shadows. 

Profiling Progression in Pseudotime: Mapping the March of Prostate Cancer 

A prostate tumor isn’t a single, unified enemy. It’s a swarm of cancer cells, each mutating at its own pace and marching along its own evolutionary path. This can result in a cellular mosaic where some regions are still relatively benign, while others are advancing toward aggressive disease. This diversity within a single tumor makes it incredibly difficult to assess how aggressive the cancer really is, especially in its early stages. That complexity has long stood in the way of developing reliable diagnostic tools that can detect high-risk prostate cancer before it progresses. 

To address this challenge, researchers at Xuzhou Medical University in China, the Karolinska Institutet in Sweden, and other institutions, published a new study in the AACR journal Cancer Research in which they analyzed tumors from more than 2,000 prostate cancer patients across three major datasets. They used spatial transcriptomics to map which genes are active within different regions of the tumor, “pseudotime” analysis to reconstruct the stepwise evolution of cancer cells, and machine learning to uncover consistent patterns of progression across samples. By tracing how different regions of the tumor diverge along distinct molecular paths, the team aimed to capture the hidden dynamics that shape how prostate cancer unfolds. Ultimately, stitching all of this information together enabled the researchers to build a dynamic model of prostate tumor progression.

Crucially, they also determined that biomarkers related to some of these molecular signals could be detected in blood and urine, offering a potential path toward noninvasive diagnostics that reflect the tumor’s internal complexity, and one that could help clinicians detect aggressive prostate cancers earlier and more precisely. Rather than relying on static snapshots, this study offers a roadmap of how prostate cancer evolves over time and space, potentially transforming how we diagnose and treat the disease before it takes a dangerous turn.