Matrix nanoalignment programs macrophage vesicular immunity through TRPV2 mechanogating.

The extracellular matrix (ECM) undergoes extensive architectural remodeling during tumor progression, generating nanoscale alignment cues that profoundly influence behaviors of immune cells. However, whether ECM nanoarchitecture directly programs their immune secretory functions remains poorly defined. Here, we develop a magnetically switchable hydrogel that enables reversible, on-demand modulation of nanoscale ligand alignment without altering bulk stiffness or composition. Using this platform, we uncover a mechanotransduction pathway in tumor-associated macrophages (TAMs) whereby matrix nanoalignment enhances integrin β1-dependent mechanosensing and transient receptor potential cation channel subfamily V member 2 (TRPV2)-dependent Ca2+ signaling, thereby promoting phosphoinositide 3-kinase (PI3K)-Ras-related protein 11a (Rab11a)-associated small extracellular vesicle (sEV) release by approximately tenfold. Beyond increasing vesicle output, PI3K-mechanistic target of rapamycin complex 2-associated signaling altered the particle-normalized cargo profile of sEVs, with preferential enrichment of immunoregulatory molecules, including M2-promoting cytokines and miR-181a-5p. These sEVs reprogram macrophages toward an immunosuppressive M2-like phenotype, suppress cytotoxic CD8+ T-cell infiltration, and accelerate melanoma progression in vivo. Importantly, selective disruption of the TRPV2-Rab11a axis or pharmacological attenuation of ECM remodeling restores antitumor immunity and restricts tumor growth. Together, our findings demonstrate that ECM nanoarchitecture is sufficient to regulate macrophage sEV programming in a defined matrix environment and identify TRPV2-associated mechanotransduction as a potential therapeutic vulnerability in matrix-remodeled tumors.