Nucleus-targeted ruthenium(II) complex triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy...

A significant challenge in the treatment of melanoma with immune checkpoint blockades (ICBs) is the limited T cells response often observed in immunologically "cold" tumors. By leveraging the immunogenicity of immunogenic cell death (ICD), which increases the susceptibility of tumor cells to ICBs, this study investigated the potential of a nucleus-targeted ruthenium(II) complex (Ru1) as an inducer of ICD. Treatment with Ru1 induced DNA damage in melanoma cells, activating the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway. This triggered endoplasmic reticulum (ER) stress, leading to ICD. Ru1-treated dying melanoma cells exhibited characteristics such as cell exposure of calreticulin (CRT) on the cell surface, release of adenosine triphosphate (ATP), and secretion of high-mobility group box 1 (HMGB1). Vaccination with Ru1-treated, dying melanoma cells elicited robust antitumor immune responses, as evidenced by CD8⁺ T cells activation, reduced Foxp3⁺ T cells count, and the development of a memory immune response that protected mice from subsequent melanoma challenges. Combining Ru1 with anti-PD-1 therapy significantly promoted T cells infiltration, enhanced dendritic cell activation, and reduced tumor-associated immunosuppressive factors, indicating a reprogramming of the tumor microenvironment. These findings suggest that Ru1 is a promising therapeutic agent for treating "cold" tumors in cancer chemoimmunotherapy.