A thylakoid-based immunometabolic reprogramming platform for ultrasound-activated extracellular matrix remodeling and antitumor immunity

The infiltration and functional persistence of effector T cells (Teffs) are severely constrained by a self-sustaining suppressive circuit comprising physical, metabolic, and immunological barriers. Here, we report a thylakoid-based immunometabolic regulatory platform (TIMR) that delivers arginine to dismantle the circuit. Following administration, thylakoids reprogram tumor-associated macrophages from arginine-consuming suppressors into nitric oxide (NO)-producing effectors. The resulting NO normalizes tumor vasculature and suppresses fibroblast-driven fibrosis, thereby alleviating extracellular matrix (ECM)-mediated physical barriers. Concurrently, thylakoid-mediated sonodynamic therapy generates reactive oxygen species that react with NO to form peroxynitrite (ONOO⁻), which inhibits tumor glycolysis and induces ECM degradation, preventing re-establishment of dense ECM. The coordinated collapse of metabolic, physical, and immunological constraints creates permissive immune niches that support Teff survival and functional maintenance. Moreover, ONOO⁻-induced immunogenic cell death activates adaptive immunity, enabling robust Teff expansion and sustained infiltration into tumors. Overall, TIMR provides a promising platform for overcoming immune resistance in solid tumors.