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

Abstract 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) 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 (MHC-I) on tumor cells, expand tumor-reactive T-cell receptor (TCR) 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.