A nanocomposite hydrogel enabling spatial redox compartmentalization for endogenous Cu(I) hijacking and durable cuproptosis-mediated tumor vaccination.

Cuproptosis-based in situ tumor vaccination provides a unique opportunity to transform tumor destruction into systemic antitumor immunity. However, the oxidative stress required for efficient tumor killing simultaneously disrupts immune competence through copper toxicity and immunosuppressive remodeling. Herein, we develop a spatial redox compartmentalized nanocomposite hydrogel platform to resolve this paradox by selectively amplifying intracellular cuproptosis while preserving the extracellular immune niche. Following peritumoral co-injection of gallic acid-grafted chitosan (CS-GA), dopamine-grafted oxidized hyaluronic acid (OHA-DA), and neocuproine-caffeic acid (NCP-CA) nanoparticles, the hydrogel establishes distinct redox microdomains for tumor eradication and immune protection. Specifically, NCP selectively exploits endogenous exchangeable Cu(I) pools and redirects copper toward mitochondria, where copper valence transformation and ferredoxin 1-mediated activation induce dihydrolipoamide S-acetyltransferase oligomerization, mitochondrial proteotoxic stress, and cuproptotic immunogenic cell death. Meanwhile, CA treatment was associated with increased AMPK phosphorylation and a 63.5% reduction in PD-L1 expression. Simultaneously, catechol-mediated redox cycling by CS-GA&OHA-DA continuously scavenges extracellular reactive oxygen species, alleviating oxidative immunosuppression and restoring T-cell viability to 94.4%. After 14 days of treatment, a substantial tumor regression was observed with a tumor volume reduction exceeding 64.2%. In a contralateral tumor rechallenge model, enhanced infiltration of CD8+ T-cells (40.8%) and CD8+ TEM-cells (26.4%) contributed to 75.6% inhibition of tumor recurrence and 93.3% suppression of metastasis. By exploiting endogenous copper resources rather than exogenous copper supplementation and spatially decoupling tumoricidal oxidation from immune-protective antioxidation, this hydrogel platform establishes a new approach for cuproptosis-based in situ vaccination, inducing durable antitumor immune memory and effectively preventing postoperative tumor recurrence and metastasis.