Nanoconjugate Strategy Integrating Immunogenic Cell Death Induction and Innate Immune Activation for Potent Anti-Cancer Immunity.

In vivo immune modulation can potentially benefit broader cancer patients. Efficient cross-priming of anti-tumor T cells requires "three-signal" dendritic cells (DCs) that simultaneously integrate antigenic, co-stimulatory, and migratory programs, which remains a major challenge. Here, we developed a carrier-free peptide-cyclic dinucleotide (CDN) nanoconjugate (PCN) that co-activates immunogenic cell death (ICD) in tumors and stimulator of interferon genes (STING) signaling in DCs. Library screening identified ICD-inducing peptides enriched in hydrophobic and cationic residues that promote self-assembly, cell penetration, and ICD potency. Mechanistic studies revealed peptides can trigger overlapping pyroptosis, necroptosis, and apoptosis, with lysosomal damage and cathepsin release as dominant upstream drivers. PCN promoted tumor-antigen release and facilitated cytosolic CDN delivery for robust STING activation. This dual functionality induced early cytokine and chemokine responses and generated cDC1-enriched "three-signal" migratory DCs trafficking from tumors to draining lymph nodes, resulting in enhanced antigen-specific CD8+ T-cell activation and memory formation. PCN also broadly reprogrammed the tumor microenvironment toward anti-tumor immunity. In preclinical models, PCN induced complete tumor rejection in 70% of B16-F10- or CT26-bearing mice and provided durable protection against tumor rechallenge when combined with α-PD-1.