Cobalt(III) prodrug-based nanomedicine for inducing immunogenic cell death and enhancing chemo-immunotherapy.

Despite impressive advances in immune checkpoint blockade therapy, its efficacy as a standalone treatment remains limited. The influence of chemotherapeutic agents on tumor immunotherapy has progressively come to light in recent years, positioning them as promising contenders in the realm of combination therapy options for tumor immunotherapy. Herein, we present the rational design, synthesis, and biological evaluation of the first example of a Co(III) prodrug (Co2) capable of eliciting a localized cytotoxic effect while simultaneously inducing a systemic immune response via type II immunogenic cell death (ICD). To enhance its pharmacological properties, a glutathione-sensitive polymer was synthesized, and Co2 was encapsulated into polymeric nanoparticles (NP-Co2) to improve efficacy. Furthermore, NP-Co2 activates the GRP78/p-PERK/p-eIF2α/CHOP pathway, thereby inducing ICD in cancer cells. This facilitates the transformation of "cold tumors" into "hot tumors" and augments the effectiveness of the PD-1 monoclonal antibody (αPD-1). In essence, this nanomedicine, utilizing Co(III) prodrugs to induce ICD, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy.