To grow, spread, and resist therapy, cancer manipulates a variety of cells and environments within the body, and breaking these interactions can help the body reject cancer, hopefully for good. At an April 29 Plenary Session of the AACR Annual Meeting 2025 in Chicago, speakers addressed the importance of the cancer ecosystem, at the tissue and systems levels, in understanding and treating malignancy.  

“We have come a long way in our understanding and appreciation that growth-permissive microenvironmental changes accompany solid tumor progression,” said Mara H. Sherman, PhD, the chair of the “Targeting the Cancer Ecosystem” Plenary Session. “What we’ve really come to appreciate in the last decade is that this cancer ecosystem extends beyond the local microenvironment and really acts at the level of the host,” added Sherman, who is from Memorial Sloan Kettering Cancer Center.

Layers of heterogeneity

Yardena Samuels, PhD, of the Weizmann Institute of Science, discussed how heterogeneity within tumors shapes the immune response and strategies for taking advantage of this phenomenon therapeutically.

Her group showed that the degree of genetic and genomic heterogeneity can influence tumor aggression, with more homogeneous tumors being associated with therapeutic resistance. Her team identified the secreted migration inhibitory factor (MIF) that appears to promote immunosuppression and an aggressive phenotype among these patients, even when its expression is limited to half of the clones.

She also addressed the challenges of targeting heterogeneity within the immunopeptidome, to enhance the efficacy of immunomodulatory therapies, and described a strategy that identified cancer-associated antigens. 

Disrupting protein translation by knocking out TYW2 led to the production of aberrant proteins, she explained, which appeared to stimulate strong antitumor immune responses. Patient data further supported TYW2’s potential as a therapeutic target, according to Samuels.

“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 added. 

Defining immunological archetypes in cancer

The immune system has numerous functions, including establishing homeostasis and healing wounds. Archetypes defined by these functions can also describe the behavior of the immune system in cancer, according to Matthew F. Krummel, PhD, of the University of California, San Francisco. 

By clustering tumor microenvironments according to gene expression and cell composition, Krummel and his team uncovered biases that led populations of tumors to look similar, immunologically speaking, defining 12 archetypes. In kidney cancer, for example, one archetype resembled the conditions of chronic viral infection. Looking at archetypes in both human tumors and those in 15 frequently used mouse models revealed some notable differences, with most mouse microenvironments showing little immune infiltration.

Ultimately, to capture more archetypes, we will need better models, said Krummel, who envisioned archetype-based pairing of patients with certain therapies that could optimize outcomes. Currently, Krummel and his team are combing data from clinical trials testing TREM antibodies. 

Spatial patterns matter for immunity

Kurt A. Schalper, MD, PhD, of Yale University, discussed the importance of spatial relationships in the interactions between tumor and immune cells, and ways to enhance these interactions to counter tumor growth. 

In lung cancer, he and colleagues found that spatial heterogeneity affected tumor responses to therapy, linking higher baseline heterogeneity among T and B cells with poor outcomes after immunotherapy alone and as part of a combination approach. 

With his team’s own three-dimensional analytical method, they compared spatial patterns in primary versus metastatic lung tumors, finding that as tumors metastasize they evade immunity more effectively and change the structure of their microenvironment.

Tumors that excluded immune cells from infiltrating responded poorly to immunotherapy, which likely occurs through an active mechanism, according to Schalper, who said “it can actually be mediated by these molecules we call T cell excluders, that have high diagnostic and therapeutic potential.”

Lastly, he showed that lower TAP transporter expression by tumor cells interfered with T cells’ ability to recognize tumor cells, and their team identified compounds that could restore TAP expression and antitumor activity. 

Multiple perspectives on metastatic dissemination 

Understanding metastasis means considering the whole cancer ecosystem, from the metastatic cell to the patient’s environment, according to Mariam Jamal-Hanjani, MD, PhD, of University College London, who presented findings from longitudinal studies of patients with lung cancer. 

The more metastases they sampled, the more evidence she and her colleagues found of multiple clones seeding the spread of the cancer. This metastatic potential appeared linked to chromosomal instability. 

Clones differ based on where they establish themselves, with different metastatic sites seemingly linked with unstable chromosomal characteristics. Distal metastases and higher chromosomal instability are both associated with worse responses to treatment, Jamal-Hanjani noted.

Additional analysis revealed that body composition at diagnosis may predict the development of cachexia, which often accompanies cancer and was seen more frequently in those with local and distal metastases, and that metastatic tumor microenvironments appear to converge and shape the evolution of surrounding somatic tissues.

“To understand the development of metastases in cancer evolution, we cannot exclude what is happening in background normal tissues,” she said. 

The recording of the full session is available for registered Annual Meeting attendees through October 2025 on the virtual meeting platform.