AACR Annual Meeting 2025 Plenaries: Cancer Evolution, Tumor Microenvironment, Drugging KRAS, and More

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.