Tumor immunotherapy is a promising cancer treatment strategy, but its efficacy is often constrained by the immunosuppressive tumor microenvironment and insufficient innate immune activation. Engaging the cGAS–STING pathway can enhance antitumor immunity and reprogram the tumor microenvironment. Celastrol (CEL), a monomer derived from Tripterygium wilfordii , can destabilize mitochondrial membranes and promote mitochondrial DNA (mtDNA) release, thereby activating the cGAS–STING pathway. However, its lack of mitochondrial accumulation results in modest immunostimulatory activity and limited translational potential. Here, we engineer a mitochondria-targeted, ATP-responsive metal–polyphenol network (CEL/mMPNs) for intratumoral delivery of CEL. Upon triphenylphosphonium-mediated mitochondrial accumulation, high levels of intracellular ATP triggers in situ CEL release, causing mitochondrial membrane depolarization, mtDNA leakage into the cytoplasm, and robust cGAS–STING activation in cancer cells. These events collectively drive mitochondria-dependent apoptosis and immunogenic cancer cell death. In animal studies, CEL/mMPNs markedly inhibited tumor growth and converted the tumor microenvironment from “cold” to “hot” state, characterized by enhanced tumor antigen presentation and increased infiltration of cytotoxic T cells. Moreover, when combined with programmed cell death protein-1 blockade, CEL/mMPNs further suppressed postoperative tumor recurrence, reduced immunosuppressive cell populations, and generated durable immune memory against residual cancer cells. Collectively, these findings identify CEL/mMPNs as a potent platform to augment tumor immunotherapy via mitochondria-driven innate immune activation. • Developed mitochondria-targeted, ATP-responsive metal–polyphenol networks based on natural polyphenols for precise, on-demand drug delivery and release in cancer cells. • Identified celastrol as a mitochondria-localized innate immune activator that disrupts mitochondrial membrane stability to trigger mtDNA leakage and robust cGAS–STING activation. • Integrated mitochondrial dysfunction–driven immunogenic cell death with endogenous cGAS–STING activation to remodel tumor microenvironment and potentiate immunotherapy.
Zhang et al. (Sun,) studied this question.