Reprogramming of the tumor microenvironment using a PCN-224@IrNCs/d-Arg nanoplatform for the synergistic PDT, NO, and radiosensitization therapy of breast cancer and improving anti-tumor immunity

The low X-ray attenuation coefficient of tumor soft tissue and the hypoxic tumor microenvironment (TME) during radiation therapy (RT) of breast cancer result in RT resistance and thus reduced therapeutic efficacy. In addition, immunosuppression induced by the TME severely limits the antitumor immunity of radiation therapy. In this paper, we propose a PCN-224@IrNCs/D-Arg nanoplatform for the synergistic radiosensitization, photodynamic, and NO therapy of breast cancer that also boosts antitumor immunity (PCN = porous coordination network, IrNCs = iridium nanocrystals, D-Arg = D-arginine). The local tumors can be selectively ablated via reprogramming the tumor microenvironment (TME), photodynamic therapy (PDT) and NO therapy, and the presence of the high-Z element Ir that sensitizes radiotherapy. The synergistic execution of these treatment modalities also resulted in adapted antitumor immune response. The intrinsic immunomodulatory effects of the nanoplatform also repolarize macrophages toward the M1 phenotype and induce dendritic cell maturation, activating antitumor T cells to induce immunogenic cell death as demonstrated in vitro and in vivo. The nanocomposite design reported herein represents a new regimen for the treatment of breast cancer through TME reprogramming to exert a synergistic effect for effective cancer therapy and antitumor immunity.