Chemo-metallo nanodrivers for spatiotemporally controlled in situ vaccination

In situ cancer vaccines exhibit promising therapeutic potential; however, their efficacy is constrained by limited antigen release, suboptimal spatiotemporal immune coordination, and adaptive immune resistance. In this study, we identify zinc ions (Zn²⁺) as synergistic agents with chemotherapeutics in modulating PANoptosis and immune signaling pathways. Capitalizing on this concept, a chemo-metallic nanodriver was developed for effective in situ cancer vaccination. This system used zinc-aluminum layered double hydroxides as the structural base and efficiently loaded cisplatin (DDP) and indocyanine green via coordination-driven polymerization, forming a spatiotemporally controllable nanodriver, which facilitated the simultaneous release of drug and metal ions upon photoactivation. The released Zn²⁺ specifically disrupted zinc homeostasis in tumor cells, inducing mitochondrial dysfunction. This effect acted in concert with DDP-mediated DNA damage, not only effectively activating the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway but also promoting the assembly and activation of AIM2-PANoptosome complex to execute PANoptosis. This STING-PANoptosis cascade led to a burst release of damage-associated molecular patterns, markedly enhanced dendritic cell maturation, and stimulated the secretion of pro-inflammatory cytokines. Furthermore, the nanodriver elicited a robust antitumor immune response and established durable immune memory in mouse models. These findings not only provide an optimized strategy for precise immunotherapy of gastric cancer but also increase the understanding of the applications of metal ion immunology and PANoptosis in disease intervention.