ROS-sensitive nanocarriers for synergistic X-PDT/chemo/immunotherapy of triple-negative breast cancer and metastasis.

X-ray-induced photodynamic therapy (X-PDT) shows significant promise in tumor treatments due to its unlimited tissue penetration but requires delivering sensitizers to tumors. Here, we engineered photosensitizer verteporfin (VP) and T-lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitor OTS964-encapsulated polymeric nanocarriers (VP/OTS964@NPs) for effective tumor X-PDT, molecule-targeted therapy and inducing robust antitumor immunity for synergistic immunotherapy of low immunogenic breast tumors and their lung metastases when combined with PD-L1 blockade. The VP/OTS964@NPs are monodisperse and can be disassembled to release drugs in response to high reactive oxygen species (ROS) levels in the tumor microenvironment or generated during X-PDT. It can efficiently deliver drugs into the TOPK-high expression breast cancer cells, generate ROS and induce ICD effects. By i.v. injection, VP/OTS964@NPs efficiently accumulated in the breast tumors and effectively eradicated tumors upon X-PDT. Additionally, the VP/OTS964@NPs activated the systemic antitumor immune responses, significantly inhibited the distant breast tumors and the lung metastasis of breast tumors, and enhanced the survival rates in combination with PD-L1 blockade. This study presented a strategy for engineering nanocarriers for synergistic molecular therapy, tumor XDT and immunotherapy. STATEMENT OF SIGNIFICANCE: X-PDT is a promising therapeutic modality for cancer treatment. However, its clinical application is hindered by the limited availability of suitable sensitizers and their insufficient tumor-targeting capability. This work aims to construct ROS-sensitive nanocarriers co-loaded with the photosensitizer verteporfin and the TOPK inhibitor OTS964 to achieve synergistic X-PDT for triple-negative breast cancer. By further activating antitumor immune responses, this strategy is designed to suppress the distant and metastatic breast tumors. Overall, this work provides both a nanodrug platform and a therapeutic strategy for the treatment of poorly immunogenic solid tumors.