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.