Novel Indoleamine-2,3-Dioxygenase-Targeted Pt(IV) Prodrugs Regulate the Tumor Immune Microenvironment to Achieve Chemoimmunotherapy In Vitro and In Vivo.

Convincing evidence revealed that some platinum-based drugs could stimulate immunological recognition, thereby inducing immunogenic cell death (ICD). Indoleamine-2,3-dioxygenase (IDO) is overexpressed in tumors, which caused exhaustion of tryptophan (T-cell energy) and constructed an immunosuppressive tumor microenvironment. Herein, considering IDO inhibition to improve chemotherapy, a series of IDOi-Pt(IV) prodrugs were designed to not only target DNA and IDO but also facilitate tumor-antigen exposure and immunomodulation. The optimal IDOi-Pt(IV) prodrugs (named compound 10) significantly enhanced intracellular accumulation 22.4-fold and cytotoxicity 61.75-fold superior to cisplatin in HeLa cells. Moreover, immunofluorescence and enzyme-linked immunosorbent assays revealed that 10 induced reactive oxygen species-mediated endoplasmic reticulum stress and secretion of damage-associated molecular patterns, thereby presenting ICD effects. Molecular docking, enzyme inhibition, and Western blot assays demonstrated that 10 could effectively inhibit IDO1 and reverse immunosuppression, as further verified by mixed leukocyte reactions. In vivo tests showed that 10 exhibited high-efficiency and low-toxicity antitumor effects compared to cisplatin, presenting successful chemoimmunotherapy.