Mechanical Microenvironment in Tumor Immune Evasion: Bidirectional Regulation Between Matrix Stiffness and Immune Cells and Its Therapeutic Implications

Immune evasion remains a major obstacle to effective cancer immunotherapy. While the regulatory mechanisms of the tumor biochemical microenvironment are relatively well-characterized, the role of its mechanical microenvironment-particularly pathologically elevated matrix stiffness-in immune evasion remains to be fully elucidated. Immune cells, as dynamic responders within the tumor microenvironment, are not merely passive recipients of mechanical signals but also active participants in driving pathological matrix stiffening. This review focuses on the elevated matrix stiffness resulting from abnormal deposition and crosslinking of the tumor extracellular matrix, systematically elucidating how it impairs immune cell function and drives immune evasion through physical barriers and mechanotransduction. Additionally, we further propose an innovative concept: the "matrix stiffness-immune cell bidirectional regulatory axis." Dissecting this regulatory loop provides an essential mechanical perspective for understanding immune evasion and offers a conceptual framework for developing matrix-targeted strategies to enhance immunotherapy. By integrating current evidence, this review aims to clarify the role of this bidirectional axis and to identify novel therapeutic targets and strategies that may improve the efficacy of cancer immunotherapies.