A Multifunctional Nanozyme Integrating PANoptosis Induction and T-Cell Metabolic Reprogramming to Augment the Efficacy of PD-1 Inhibitors

Cancer remains a major global health burden due to its high rates of recurrence and resistance to conventional therapies. Although PD-L1/PD-1 immune checkpoint inhibitors (ICIs) have emerged as promising treatments by restoring T cell function and enhancing anti-tumor immunity, their efficacy is often limited by immunosuppressive tumor microenvironment (ITM) and metabolic adaptations that impair T cell activity. To address these challenges, we developed a novel intelligent drug delivery platform that integrates PANoptosis induction, metabolic modulation and targeted nanotherapy. Specifically, hollow mesoporous manganese dioxide (H-MnO 2 ) nanoshells were synthesized and co-loaded with SOAT1 inhibitor avasimibe (Ava). Trop2-specific targeting ligands were further conjugated to enable precise tumor localization, resulting in the multifunctional nanoplatform Ava@HM/Trop2. Upon tumor accumulation via Trop2-mediated targeting, acidic pH conditions and TME stimuli trigger rapid degradation of the H-MnO 2 nanoshells, releasing Ava and inducing PANoptosis. This process activates the cGAS-STING pathway, remodels immunosuppressive TME, mitigates lipid-induced T cell senescence, and synergizes with PD-1 blockade to potentiate anti-tumor immunity. Both in vitro and in vivo experiments demonstrate that Ava@HM/Trop2 achieves efficient tumor targeting, robust tumor cell apoptosis, and improved therapeutic outcomes. This innovative multi-modal strategy highlights a promising avenue for overcoming immunotherapy resistance and advancing the clinical management of solid tumors.