Organoplatinum(II) Type II Immunogenic Cell Death Inducers Target Protein Tyrosine Phosphatase 1B to Drive Immunogenicity

Immunogenic cell death (ICD) inducers are valuable chemotherapeutic agents that elicit protective immune responses against tumors. Although many ICD inducers have emerged in recent years, specific molecular targets directly associated with ICD remain relatively unexplored. Here, two Type II ICD inducers, <b>Pt-NHC</b> and <b>PlatinER</b> (<b>Pt-ER</b>), were validated as <i>bona fide</i> ICD inducers with the ability to establish immunity against colorectal cancer <i>in vivo</i>. Based on <b>Pt-ER</b>, several ICD-inducing photoactivable probes were designed to capture their potential targets. By integrating quantitative proteomics analysis with biochemical assays, we identified PTP1B as a direct target of <b>Pt-ER</b> that engages in ICD. Both <b>Pt-ER</b> and <b>Pt-NHC</b> were shown to directly interact with PTP1B and inhibit its enzymatic activity. The suppression of PTP1B, by either genetic knockdown or pharmacological inhibition, enhanced the immunogenicity of tumor cells by increasing surface-exposed calreticulin and phagocytosis of cancer cells. Bioinformatic analysis also revealed that PTP1B plays a role in tumor progression and immune regulation in colorectal cancer. Therefore, our study first reveals a previously unrecognized role of PTP1B in modulating ICD and highlights its potential therapeutic values in cancer chemoimmunotherapy.