Ruthenium coordinated nanohybrids modulate tumor microenvironment and potentiate amplified phototherapy augmented immunotherapy of hypoxic tumor

Hypoxic tumor microenvironment (TME) greatly limits the efficacy of photodynamic therapy (PDT) and immunotherapy. Additionally, small molecule phototherapeutic agents not only require delivery vectors due to their poor water solubility, but also suffer from poor photostability. Herein, we present a synergy of nanocatalysts-amplified PDT, sustained photothermal therapy (PTT) and robust immunotherapy for eliminating hypoxic solid tumor and preventing distant tumor metastasis by constructing the ruthenium coordinated nanohybrids (defined as RuIP) consisting of ruthenium (Ru) ions, phototherapeutic agent (IR825), and polyvinylpyrrolidone (PVP). The coordination driven self-assembly of IR825 with Ru improves the photostability of IR825 and endows it i) with high catalytic O₂ generation to alleviate tumor hypoxia and ii) antioxidant GSH depletion to promote PDT against tumor. Meanwhile, the coordination effect also enhances the photothermal conversion efficiency of IR825, especially the photothermal stability for sustained antitumor PTT. Under laser activation, self-assembled RuIP nanohybrid triggers the substantial killing of primary cancer in 4T1-bearing mice model through photodynamic and photothermal pathways, resulting in the induction of immunogenic cells death and the activation of antitumor immunity. Additionally, the catalytic O₂ generation by RuIP alleviates tumor hypoxia and modulates the hypoxia-induced immunosuppressive TME, which further downregulates the PD-L1 expression in tumor cells, re-programs macrophage phenotype, and recruits more killer immune cells. The resulting immune memory successfully suppresses distant tumors, and restrict the growth of metastatic hypoxic tumor. Therefore, RuIP nanohybrid acts as an enzyme analogue to improve the efficiency of photo-immunotherapy, providing a translatable therapeutic strategy for hypoxic tumors.