Endogenous nanoplatforms for tumor photoimmunotherapy: Hypoxia modulation and STING pathway activation

Photoimmunotherapy (PIT) holds significant promise for cancer treatment due to its spatial precision and sustained therapeutic effects. However, overcoming the immunosuppression and hypoxia of the tumor microenvironment (TME) remains a major challenge. To solve this problem, we developed a multifunctional PIT nanoplatform (BYMnNps). Its composition plays different roles: i) Biliverdin can induce mild photothermal and photodynamic therapy, enhance the penetration of nanoplatforms into tumors, and induce immunogenic cell death; ii) the immunotherapy peptide tyroserleutide induces tumor cell apoptosis and enhances tumor-specific immune responses; iii) Mn²⁺ can catalyze the generation of oxygen from hydrogen peroxide, reducing tumor hypoxia, while activating the cGAS-STING pathway, further boosting cancer immunotherapy. The nanoplatforms significantly inhibit tumor growth and increase tumor sensitivity to α-PD 1 therapy. Notably, BYMnNps also exhibit photoacoustic and magnetic resonance imaging capabilities. Overall, BYMnNps effectively counteract tumor immune suppression and alleviates TME hypoxia, demonstrating good biocompatibility and antitumor efficacy, with broad potential for precision cancer treatment guided by multimodal imaging. STATEMENT OF SIGNIFICANCE: Photoimmunotherapy holds great promise for cancer treatment due to its spatial precision and sustained therapeutic effects. However, phototherapy-induced tumor hypoxia leads to resistance, posing a significant challenge. This study utilizes endogenous photosensitizer biliverdin, immunotherapy peptide tyroserleutide, and Mn²⁺ to self-assemble into a multifunctional nanoparticle, aimed at simultaneously reversing the immunosuppression of the tumor microenvironment and alleviating hypoxia. It demonstrates good biosafety and antitumor efficacy, enhancing tumor sensitivity to α-PD1 therapy. Additionally, it exhibits photoacoustic and magnetic resonance imaging capabilities, showing broad potential for precision cancer treatment guided by multimodal imaging. It has the potential to overcome the current limitations of photoimmunotherapy, offering a new avenue for cancer treatment.