The tumor microenvironment (TME) represents a complex battlefield where immune cells engage in a delicate balance between promoting and suppressing cancer progression. At the 2025 ASCO Annual Meeting, researchers presented groundbreaking insights into how this dynamic ecosystem can be strategically manipulated to enhance immunotherapy outcomes.
The Dual Nature of the Tumor Microenvironment
The TME operates as a heterogeneous and dynamic ecosystem where immune cells and tumor cells interact in ways that either promote or suppress cancer progression. According to Judith A. Varner, PhD, from the University of California San Diego, "The [TME] is complex. 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."
Macrophages emerge as particularly significant players, comprising 30% to 60% of the tumor mass in some cancers. These cells differentiate into two distinct subgroups: M1 macrophages, which are "classically activated" and act as antitumoral agents, and M2 macrophages, which are "alternatively activated" and contain tumor-associated macrophages that facilitate progression through immunosuppression.
The physical barriers created by pro-tumor forces present additional challenges. Fibroblasts produce collagen that forms dense networks around tumors, creating barriers that physically block T-cells from entering tumor areas. Macrophages reinforce these barriers by helping fibroblasts produce collagen, while also positioning themselves strategically to prevent T-cell penetration into tumor cores.
Anti-Tumor Forces and Immune Coordination
On the opposing side, anti-tumor forces work through direct cytotoxic mechanisms. CD8+ T cells kill tumor cells by forming synapses and releasing enzymes like perforin and granzymes that break down cellular contents. Natural killer (NK) cells contribute to this anti-tumor response by working alongside T-cells to identify and eliminate malignant cells through similar cytotoxic pathways.
Pro-inflammatory M1 macrophages express lytic factors and play a dual role in recognizing pathogens and signaling the immune system by attracting T cells, B cells, and other immune effectors to the tumor site. Activated dendritic cells ensure a more targeted and sustained attack against tumor cells by priming and arming CD8+ T-cells.
The Interferon Paradox and JAK Inhibition
A critical discovery involves the dual role of interferons in the TME. Andy J. Minn, MD, PhD, from the University of Pennsylvania, explained that "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."
This activation leads to interferon generation and JAK-STAT signaling, inducing hundreds of interferon-stimulated genes (ISGs). While some ISGs are "good" and predict positive responses, "bad" ISGs predict poor treatment outcomes and are associated with tumor relapse and T-cell exhaustion.
Researchers are exploring JAK inhibitors to block chronic interferon signaling with the goal of resetting the tumor immune system state. In a clinical study, itacitinib, a JAK1-selective inhibitor from Incyte Corporation, was administered with pembrolizumab (Keytruda; Merck & Co) in patients with non-small cell lung cancer. The approach achieved an overall response rate of 67% and marked improvement in overall survival, with researchers observing that the JAK inhibitor appeared to reset T-cell differentiation away from exhaustion.
LAG3: The Third Immune Checkpoint
Beyond traditional checkpoint inhibitors, researchers are investigating LAG3 as the third immune checkpoint inhibitor after CTLA-4 and PD-1. LAG3 functions differently from other checkpoints, being rapidly shed by ADAM metalloproteases and existing as an obligate dimer. In March 2022, the FDA approved a fixed-dose combination of relatlimab (Opdualog; Bristol Myers Squibb) with nivolumab (Opdivo; Bristol Myers Squibb) for treating metastatic melanoma.
The dual blockade of PD-1 and LAG3 leads to distinct changes in CD8+ T cells, including enhanced T-cell signaling and partial reversal of exhaustion. Dario Vignali, PhD, from the University of Pittsburgh, noted that "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."
Metabolic Reprogramming and Immune Cell Function
The TME's metabolic landscape significantly impacts immune cell function. During early oncogenesis, the TME maintains an immune-promoting environment with high pro-inflammatory signals. However, as tumors progress, the environment transforms into an immunosuppressive state characterized by low glucose concentration, high fatty acid and lactic acid concentrations, low oxygen, low pH, and reduced amino acid availability.
This metabolic shift affects various immune cell populations differently. For instance, macrophages recruited to hypoxic tumor areas undergo polarization from an M1-like phenotype that promotes tumor cell destruction to an M2-like pro-tumor phenotype. Similarly, regulatory T cells, known for their immunosuppressive properties, actively suppress potent anti-tumor responses in tertiary lymphoid structures.
Therapeutic Implications and Future Directions
The evolving understanding of TME complexity continues to reshape approaches to cancer immunotherapy. Researchers emphasize that the ability to manipulate the immune microenvironment may be key to overcoming resistance and enhancing immunotherapy outcomes.
Current therapeutic strategies focus on multiple approaches: blocking chronic interferon signaling to prevent T-cell exhaustion, combining checkpoint inhibitors to create more durable immune responses, and targeting specific immune cell populations within the TME. The success of combination therapies like itacitinib with pembrolizumab and relatlimab with nivolumab demonstrates the potential for multi-target approaches.
As research progresses, the identification of "good" versus "bad" interferon-stimulated genes provides new targets for therapeutic intervention. The concept of resetting the tumor immune system state through JAK inhibition represents a paradigm shift from simply blocking inhibitory signals to actively reprogramming the immune response.
These advances highlight the importance of understanding the TME as a dynamic, interconnected system where therapeutic interventions must account for the complex interplay between multiple immune cell populations and their metabolic constraints. The future of cancer immunotherapy lies in developing sophisticated strategies that can simultaneously enhance anti-tumor forces while dismantling pro-tumor networks within the TME.
