Uncoupling tumor immunogenicity from cell death with platinum(IV)–antibody conjugates

Platinum drugs remain mainstays for solid tumors, but systemic toxicity and difficult dose finding in immunotherapy combinations limit their use. We engineer platinum(IV)-antibody conjugates [Pt-ADCs (platinum-based antibody-drug conjugates)] that confine a 'metal immune effect' to tumors while reducing off-tumor exposure. Site-specific glycoengineering installs redox-responsive Pt(IV) prodrugs at defined drug-to-antibody ratios, yielding homogeneous conjugates. Mechanistic profiling shows that cisplatin-derived, but not oxaliplatin-derived, payloads undergo efficient reductive activation in the tumor milieu; cinnamate-capped variants optimize serum stability, intratumoral release, and immunostimulatory signaling. In syngeneic models, Pt-ADCs deliver a low dose of cinnamate-capped Pt to upregulate major histocompatibility complex class I on tumor cells, expand tumor-reactive T-cell receptor clonotypes, and synergize with PD-1 blockade to suppress tumor growth, with minimal systemic toxicity. These findings position Pt-ADCs as a detoxified, immunogenic modality that uncouples immunogenic priming from high-dose cytotoxicity and offers a tractable path to rational dosing in chemo-immunotherapy combinations.