Cascade-targeting oxygen-self-supplying nano-photosensitizer for enhanced photodynamic immunotherapy of triple-negative breast cancer.

The efficacy of immunogenic photodynamic therapy (PDT) is critically limited by the inadequate tumor accumulation of photosensitizers and the resultant hypoxia in the tumor microenvironment. To address these challenges, we report a multifunctional nano-photosensitizer (TACR) constructed via a one-step self-assembly of a mitochondrial-targeting photosensitizer (TPP-Ppa), the hypoxia-relief agents (catalase and atovaquone), and a tumor-targeting ligand (RGD-PEG-BSA). TACR achieves sequential active targeting to tumor tissues and mitochondria. Crucially, it orchestrates a dual-path oxygen-economizing strategy: catalase decomposes endogenous H₂O₂ to generate O₂, while atovaquone inhibits mitochondrial respiration to reduce oxygen consumption. This localized oxygen replenishment significantly enhances the production of cytotoxic singlet oxygen by TPP-Ppa upon 660 nm irradiation, leading to potent tumor cell killing and immunogenic cell death (ICD). The elicited ICD promotes dendritic cell maturation and cytotoxic T lymphocyte activation, effectively reversing the immunosuppressive tumor microenvironment. In a murine model of triple-negative breast cancer, TACR-mediated PDT synergized with α-PD-L1 checkpoint blockade, achieving robust inhibition of both primary and distant tumor growth. This work presents a rational design of an intelligent nanoplatform that simultaneously overcomes the key barriers in PDT and effectively harnesses the immune system for combinatorial cancer therapy. STATEMENT OF SIGNIFICANCE: To address the challenges of hypoxia, immunosuppression, and metastasis in triple-negative breast cancer, a cascade-targeting and self-oxygenating nano-photosensitizer (TACR) was developed. It alleviates tumor hypoxia through a dual-action mechanism, enhancing photodynamic therapy efficacy while achieving precise tumor and mitochondrial accumulation. TACR-mediated photodynamic therapy induces immunogenic cell death and remodels the tumor microenvironment. In combination with α-PD-L1 immune checkpoint blockade, it elicits a systemic antitumor immune response, effectively suppressing both primary and distant tumors.