Ultrasound-driven mechanical immunomodulation enhances tumor treatment sensitivity: advances from tumor mechanical immunobiology to immunotherapy applications.

Tumor immunotherapy is often limited by microenvironmental heterogeneity and immune tolerance. The mechanical properties of tumors, such as matrix stiffening and elevated interstitial fluid pressure, sustain immunosuppressive programs and create physical barriers that restrict the infiltration of drugs and immune cells, leading to poor therapeutic responses. Targeting these mechanical constraints has thus emerged as a key strategy for sensitizing tumors to immunotherapy. As a modality that generates mechanical stimuli, ultrasound can modulate immune cells and the tumor microenvironment, offering a noninvasive and clinically promising approach to deliver programmable mechanical stimuli. By generating mechanical stimuli through acoustic radiation forces, acoustic streaming, and cavitation, ultrasound provides a basis for linking acoustic parameters with immunophenotypic outcomes. Current evidence supports two principal mechanisms through which ultrasound modulates immune responses: first, by directly regulating immune cell behavior via mechanosensitive channels-enhancing calcium signaling, promoting integrin-mediated adhesion, and triggering cytoskeletal remodeling; second, by indirectly boosting immunity through remodeling the tumor microenvironment-improving vascular permeability, loosening physical barriers, and alleviating hypoxic and metabolic stress. In this review, we summarize recent advances in ultrasound-driven mechanical immunomodulation in tumor treatment, with a focus on its bioeffects on immune cells and the tumor microenvironment, as well as the underlying molecular mechanisms revealed by advanced multi-omics techniques. Future efforts to address challenges such as dosimetry standardization, cavitation reproducibility, targeting accuracy, balancing efficacy with safety, and cell-type-specific heterogeneity will help optimize the synergy between ultrasound and immunotherapy and accelerate its clinical translation.