Abstract / Summary
The extracellular matrix (ECM) is a dynamic and functionally active component of the tumor microenvironment that critically regulates immune cell trafficking, activation, and persistence. Rather than serving solely as a structural framework, ECM remodeling through collagen reorganization, proteoglycan-dependent chemokine sequestration, and fibroblast-driven matrix stiffening actively contributes to immune exclusion and evasion in solid tumors. This review integrates emerging mechanistic insights into how ECM composition, architecture, and mechanical properties shape spatial immune exclusion, T cell dysfunction, and immune-checkpoint regulation through mechanotransduction, metabolic reprogramming, and altered cytokine and chemokine signaling. Particular emphasis is placed on the coordinated activities of distinct ECM components and cancer-associated fibroblast subtypes in establishing spatially restricted immunosuppressive niches that limit antitumor immunity and therapeutic responsiveness. ECM-targeted therapeutic strategies are critically evaluated by integrating their mechanistic rationale, preclinical efficacy, clinical trial outcomes, and current stage of translational development. The importance of biomarker-guided patient stratification is also highlighted for identifying tumors most likely to benefit from ECM-directed interventions, particularly in combination with immune-checkpoint blockade and other immunotherapies. Finally, recent advances in spatial transcriptomics, proteomics, matrix imaging, and ECM-derived circulating biomarkers are discussed as tools to refine therapeutic targeting, monitor matrix remodeling, and predict treatment response. By conceptualizing the ECM as an active immunoregulatory network rather than a passive physical barrier, the review provides a mechanistic and translational framework for developing next-generation, ECM-informed cancer immunotherapies.