Abstract:Significant breakthroughs have been made in tumor immunotherapy, yet its clinical efficacy remains limited by the immunosuppressive nature of the tumor microenvironment (TME). While previous research has focused on the biochemical regulatory networks within the TME, recent studies have demonstrated that biomechanical factors, by remodeling the physical properties of the extracellular matrix (ECM) and the cellular mechanosensing system, constitute a new dimension of immune regulation independent of biochemical signals. This review systematically summarizes the mechanisms underlying the interplay between biomechanics and tumor immunity, such as the regulation of immune checkpoint expression via the integrin/YAP pathway, T cell migration disorders, and macrophage polarization, thereby proposing a novel "mechano-intervention?–?immune regulation" strategy for cancer therapy. We further summarize cutting-edge technologies in tumor immunotherapy, including mechanosensitive molecule gene editing, nanoparticles, and smart materials for remodeling the TME, and propose a systematic solution of "mechano-design?–?precision delivery?–?immune regulation", which may provide a new theoretical basis for developing novel tumor immunotherapies. From a clinical translational perspective, elucidating biomechanical mechanisms offers new targets (e.g., YAP, PIEZO1) to overcome immunotherapy resistance. Mechanical intervention techniques, such as nanoparticle-mediated matrix softening and magneto-mechanical disruption of tumor membrane structures, can synergize with existing immunotherapies (e.g., CAR-T, immune checkpoint inhibitors) to improve response rates in patients with solid tumors. In the future, individualized diagnosis and combination therapy strategies based on mechanomics may represent an innovative breakthrough in precision cancer immunotherapy.