An in situ forming immunomodulatory hydrogel reinvigorates exhausted CD8+ T cells via preserving their mitochondrial fitness.

CD8+ T cell exhaustion driven by mitochondrial dysfunction remains a major barrier to effective cancer immunotherapy. Here, we report an in situ forming d-α-tocopheryl polyethylene glycol succinate (TPGS)-based hydrogel [multifunctional thermosensitive composite gel (MTC Gel)] that reinvigorates exhausted CD8+ T cells by preserving mitochondrial fitness through a two-pronged strategy. After intratumoral injection, MTC Gel rapidly undergoes gelation at physiological temperature and dissociates to generate a high local concentration of TPGS, which targets cancer cell mitochondria to trigger prodeath mitophagy. This process induces robust immunogenic cell death (ICD) and blocks tunneling nanotube-mediated mitochondrial hijacking. Meanwhile, NLG919-loaded hybrid nanoparticles released from MTC Gel synergistically restore mitochondrial biogenesis in CD8+ T cells suppressed by indoleamine 2,3-dioxygenase 1. Across multiple murine tumor models, MTC Gel reprograms T cell immunity by reducing CD8+ T cells exhaustion while enhancing effector and cytotoxic functions, thereby eliciting potent tumoricidal activity. These findings highlight this rationally designed hydrogel system as a clinically translatable platform for next-generation ICD-based cancer immunotherapies.