Agent-based modeling of tumor microenvironment suppression reveals the dominant barriers to anti-tumor immunity.

Cancer progression is driven by a tumor microenvironment (TME) that suppresses anti-tumor immunity through structural, cellular, and metabolic barriers. We developed a computational model to compare the relative impact of four major suppressive mechanisms: extracellular matrix (ECM) remodeling, PD-1-mediated checkpoint inhibition, regulatory T cell (Treg) suppression, and glucose-related metabolic limitation. Model parameters were calibrated using experimental data to ensure biological fidelity and predictive accuracy. Simulations reveal that ECM-mediated immune exclusion is the dominant barrier to anti-tumor activity, followed by PD-1 signaling, Treg suppression, and glucose deprivation. Physical restriction of immune cell access to the tumor represents the primary bottleneck, with other suppressive mechanisms exerting stronger effects only after immune cells have already infiltrated the tumor niche. Interventions targeting ECM normalization produced the greatest reduction in tumor burden and were associated with increased cytotoxic T cells and mature dendritic cells, indicating a shift toward a more immunostimulatory microenvironment. Combination strategies involving ECM targeting and checkpoint blockade further enhanced anti-tumor effects, supporting the idea that relieving stromal exclusion can improve the effectiveness of downstream immunotherapies. Overall, our findings highlight the layered and cooperative nature of TME-mediated immune evasion and suggest that therapies aimed at disrupting ECM-driven immune exclusion may provide the most effective entry point for restoring anti-tumor immunity in solid tumors. These results offer a mechanistic rationale for prioritizing ECM-normalizing strategies in combination with checkpoint inhibition.