GSH-Triggered Self-Cascading Nanoreactor Integrates Efficient ICD Induction and Immune Checkpoint Blockade for Pancreatic Cancer Therapy

Chemodynamic therapy (CDT) is currently constrained by insufficient endogenous H 2 O 2 , enhanced antioxidant defense, weakly acidic conditions in pancreatic cancer. However, the CDT's immunotherapeutic potential hinges on radical-mediated immunogenic cell death (ICD) induction, motivating development of potent self-cascading radical nanogenerators. Herein, this work engineers carrier-free nanoparticles (IAA NPs) through metal-organic self-assembly of Fe 3+ , artesunate (AS) and PD-L1 antibody (αPD-L1), exhibiting high drug loading (AS: 80.62%, Fe 3+ : 4.57%, and αPD-L1: 14.81%), excellent stability and GSH/pH-dependent drug release. IAA NPs achieve GSH-triggered Fe 3+ reduction to Fe 2+ , catalyzing AS decomposition into carbon-centered radicals, with this radicalogenesis being H 2 O 2 /pH-independent while concurrently depleting intratumoral GSH antioxidant. These free radicals effectively induce ICD via apoptosis pathway, eliciting CRT exposure, HMGB1/ATP release, and efficient DC maturation. In Pan02 tumor-bearing mice, IAA NPs efficiently triggers ICD, promoting DC maturation, intratumoral CD4 + /CD8 + T-cell infiltration, and markedly inhibiting tumor growth. Concurrently, αPD-L1 blocks PD-1/PD-L1 pathway and restores T cell recognition, thereby enhancing the antitumor immune response. In addition, the favorable pharmacokinetic profiles, coupled with inherent biocompatibility and biosafety, collectively enhance IAA NPs’ translational potential. Basically, IAA NPs represent a novel strategy to improve combination chemodynamic-immunotherapy through radical-induced ICD and PD-L1 blockade.