The tumor microenvironment, or TME, is a complex arena where immune cells and tumor cells engage in a constant tug-of-war. this interaction can either fuel cancer’s progression or suppress it. Recent research presented at the 2025 ASCO Annual Meeting underscores the intricate role of the immune system within the TME, highlighting the delicate balance between pro-tumor and anti-tumor forces that ultimately dictate therapeutic outcomes. Understanding and manipulating this environment is becoming increasingly crucial for enhancing the effectiveness of immunotherapy.

The Two Faces of the Immune System in the TME

The TME is far from a simple battleground. It’s a dynamic ecosystem with both allies and enemies of cancer cells. The [TME] is complex,” explained dr. Judith A. Varner, PhD, BS, from the University of California San Diego. On the one hand,we have pro-tumor forces in which a number of immune cell types,such as pro-tumor macrophages,regulatory B-cells,CD4+ T-cells,known as regulatory T-cells [Tregs] and fibroblasts that produce collagen,all work together to stimulate tumor growth and metastasis.

Pro-Tumor Forces: Aiding and Abetting Cancer

• Macrophages: These immune cells, particularly the M2 subgroup, suppress T-cell function, creating an environment that shields tumor cells from attack. Macrophages can comprise a substantial portion of the tumor mass, sometimes ranging from 30% to 60%.
• Fibroblasts: These cells produce collagen,forming a dense network around tumors that acts as a physical barrier,preventing T-cells from reaching their target. Macrophages further assist fibroblasts in collagen production, reinforcing this protective shield.
• Regulatory B Cells and Tregs: These cell types contribute to immune suppression, protecting tumor cells and hindering effective anti-tumor immune responses.

Anti-Tumor Forces: The Body’s Defense Line

• CD8+ T Cells: These cells directly kill tumor cells by releasing enzymes like perforin and granzymes, breaking down their cellular contents.
• Effector Cytolytic T-Cells: Similar to CD8+ T cells, these cells produce enzymes that destroy cancer cells as part of an active immune assault.
• Natural Killer (NK) Cells: NK cells work alongside T-cells to identify and eliminate malignant cells thru similar cytotoxic pathways.
• Pro-inflammatory M1 Macrophages: These macrophages express lytic factors and signal the immune system by attracting T cells, B cells, and other immune effectors to the tumor site.
• Activated Dendritic cells: These cells present tumor antigens to T-cells, initiating immune responses and ensuring a targeted and sustained attack against tumor cells by priming and arming CD8+ T-cells.

The interferon Paradox: Friend or Foe?

Interferons,cytokines released during infections and within the TME,have a dual nature. While they can initially promote T-cell priming and generate effector and memory populations to eliminate pathogens, chronic interferon exposure can lead to T-cell exhaustion and inflammatory memory in cancer cells.

Aberrant nucleic acids-whether it’s the DNA from micronuclei or the double-stranded RNA generated by these endogenous and derepressed retroviruses-can activate the same type of pattern recognition receptors or sensors that are present in the cytosol that normally engage viral RNA or viral DNA,” explained Dr. Andy J. Minn,MD,PhD,from the University of Pennsylvania. So, this leads to the generation of interferon and then activates JAK [Janus kinase] stat signaling and the induction of hundreds of genes that are known as interferon-stimulated genes, or ISGs, manny of which have direct antiviral effects or effects on the immune system.
andy J. Minn, MD, PhD, University of Pennsylvania

Some interferon-stimulated genes, or ISGs, are beneficial, predicting positive responses and enhancing initial immune activation. Others, however, predict poor treatment outcomes, promote immune evasion, and are associated with tumor relapse and T-cell exhaustion. What we believe happens is that cancer cells, when they’re exposed to chronic levels of interferon, in this case, interferon gamma, that leads to the cancer cells adapting or undergoing epigenetic reprogramming, very similar to inflammatory memory,” said Dr. minn.

Strategies to Manipulate the TME for Therapeutic Gain

Researchers are actively exploring ways to manipulate the TME to improve immunotherapy responses. These strategies include:

• JAK Inhibitors: These drugs, such as itacitinib, aim to block chronic interferon signaling, resetting the tumor immune system state and preventing T-cell exhaustion.In a study combining itacitinib with pembrolizumab in patients with non-small cell lung cancer, researchers observed a 67% overall response rate and improved overall survival. the researchers observed that the addition of the JAK inhibitor appeared to reset T-cell differentiation, steering it away from exhaustion.
• LAG3 inhibitors: LAG3 is considered the third immune checkpoint inhibitor after CTLA-4 and PD-1. The FDA approved a fixed-dose combination of relatlimab with nivolumab for the treatment of metastatic melanoma, marking a meaningful milestone in LAG3-targeted immunotherapy. Our data suggested that PD-1 generates sprinters that function effectively in a short period of time, perhaps [without] the durability required for a long-term fight against cancer, whereas this PD-1 LAG3 combination produced marathon runners that had durability, giving rise to increased efficacy over time,” said Dr.Dario Vignali, PhD, from the University of pittsburgh.

The Future of Cancer Immunotherapy

The evolving understanding of the TME is reshaping approaches to cancer immunotherapy. The ability to manipulate the immune microenvironment may be key to overcoming resistance and enhancing immunotherapy outcomes. As research progresses, expect to see more targeted therapies designed to modulate the TME and unleash the full potential of the immune system against cancer.