Mechanical properties of the tumor microenvironment: drivers of immunotherapy resistance in solid tumors

The limited efficacy of immunotherapy in solid tumors is increasingly recognized to reflect not only molecular and cellular immune suppression, but also profound mechanical abnormalities within the tumor microenvironment (TME). Emerging evidence indicates that extracellular matrix (ECM) stiffening and architectural remodeling, altered cellular stiffness, elevated solid stress, abnormal fluid shear stress, and increased interstitial fluid pressure (IFP) critically shape antitumor immunity and contribute to immunotherapy resistance. In this review, we summarize these major mechanical features and critically examine how they regulate the cancer-immunity cycle, including tumor-antigen release, antigen presentation, T-cell priming and activation, immune-cell trafficking and infiltration, tumor-cell recognition, and cytotoxic killing. We further highlight that tumor mechanical properties can function as mechanical immune checkpoints that promote immune evasion. Finally, we evaluate emerging strategies that target ECM remodeling, cancer-associated fibroblasts, vascular dysfunction, IFP, and mechanotransduction pathways to improve immunotherapy efficacy. The therapeutic evidence discussed is predominantly derived from preclinical studies. Overall, integrating tumor mechanical properties into cancer immunology provides a broader framework for understanding immunotherapy resistance and developing rational combination strategies for solid tumors.