An endoplasmic reticulum-targeting iridium(III) complex induces immunogenic cell death in melanoma cells and enhances anti-PD-1 immunotherapy by remodeling tumor microenvironment

One of the major challenges for immune checkpoint blockades (ICBs) lies in melanoma with limited T cell responses or immunologically "cold" tumors. Inspired by the immunogenicity of immunogenic cell death (ICD) that renders tumor cells sensitive to ICBs, in the present study, an endoplasmic reticulum (ER) targeting iridium(iii) metal complex (IrC) was investigated as an ICD inducer. It was found that the IrC-treated tumor cells showed the hallmarks of ICD, including cell surface exposure of the endoplasmic reticulum protein calreticulin (CRT), secretion of high mobility group box 1 protein (HMGB1), and release of adenosine triphosphate (ATP). The vaccination of syngeneic immunocompetent mice with IrC-treated dying cells resulted in anti-tumor immunity with CD8(+) T cell response, Foxp3(+) T cell depletion, and memory immunity effect. Furthermore, tumor-bearing mice treated with IrC + anti-PD-1 combination therapy showed proinflammatory cytokines secretion, increased dendritic cells (DCs) activation, and CD8(+) T cell infiltration within the tumor, indicating that the combinatorial therapy reconstructs the tumor microenvironment (TME) and converts an immune "cold" tumor into a "hot" one. This work provides a promising strategy for cancer chemo-immunotherapy.