PANoptosis-triggering GA-based biomimetic nano-prodrug remodels the tumor microenvironment to enhance antitumor immunity.

Gambogic acid (GA) exhibits potent antitumor effects through multiple synergistic mechanisms, making it a promising candidate for adjuvant therapy in refractory cancers. However, its clinical translation has been hindered by poor aqueous solubility, low bioavailability, and systemic toxicity. In this study, we develop a dual-responsive biomimetic nano-prodrug (CM@pGGH) that addresses these limitations and facilitates effective, tumor-targeted therapy. CM@pGGH is synthesized by conjugating GA and hydroxychloroquine (HCQ)-an FDA-approved antimalarial and immunomodulator-to polyglutamic acid (PGA) using disulfide and ester linkages, followed by incorporation of a hybrid membrane derived from tumor cell and macrophage. The dual linkages allow for tumor microenvironment-specific release of both drugs under reductive and acidic conditions. Additionally, the hybrid membrane provides tumor-homing capability and helps evade immune clearance. CM@pGGH induces PANoptosis, a recently characterized form of regulated cell death that integrates pyroptosis, apoptosis, and necroptosis, thereby activating multiple cytotoxic pathways. In vivo, CM@pGGH reprograms the tumor immune microenvironment by repolarizing tumor-associated macrophages to a pro-inflammatory M1 phenotype and promoting CD8+ T-cell infiltration, resulting in significant PANoptosis-driven immunogenic cell death (ICD) and sustained antitumor immunity. These findings highlight a dual-prodrug and immune-reprogramming strategy with potential for treating refractory cancers.