Photoactivated Ruthenium–Platinum Complex Enhances Immune Checkpoint Blockade Therapy by Upregulating MHC-I Expression and Inducing Immunogenic Cell Death

Cancer immunotherapy holds great promise but is often limited by tumor immune evasion via major histocompatibility complex class I (MHC-I) downregulation. To overcome this, we rationally designed a trinuclear ruthenium-platinum complex (TriRuPt) that leverages metal-enhanced photooxidation and exhibits light-induced nuclear translocation. As a photosensitizer in photodynamic therapy (PDT), TriRuPt generates reactive oxygen species to disrupt cellular homeostasis and triggers dual immunomodulatory effects: (i) MHC-I upregulation, enhancing T cell recognition and activation, and (ii) induction of immunogenic cell death (ICD), promoting dendritic cell-mediated antigen presentation and amplifying antitumor immunity. Furthermore, TriRuPt-mediated PDT synergizes with immune checkpoint inhibitors, significantly suppressing tumor growth in vivo, reprogramming the tumor microenvironment, and enhancing adaptive immune responses. This study establishes a metal-based dual immunomodulatory strategy to potentiate immune checkpoint blockade therapy and reveals an underexplored immunoregulatory property of transition metal complexes, providing a promising strategy to overcome tumor immune evasion and resistance in cancer immunotherapy.