Nanodrugs Reprogram Cancer-Associated Fibroblasts and Normalize Tumor Vasculatures for Sequentially Enhancing Photodynamic Therapy of Hepatocellular Carcinoma

BACKGROUND: The failure of cancer photodynamic therapy (PDT) is largely ascribed to excessive stroma and defective vasculatures that restrain the photosensitizer permeation and the oxygen perfusion in tumors. METHOD AND RESULTS: In this study, a nanodrug that integrated the cancer-associated fibroblast (CAF) regulation with tumor vessel normalization was tailored to sequentially sensitize PDT. The nanodrug exhibited high targeting towards CAFs and efficiently reversed the activated CAFs into quiescence, thus decreasing collagen deposition in the tumor microenvironment (TME), which overcame the protective physical barrier. Furthermore, the nanodrug regulated vascular endothelial cells and restored the tumor vasculatures, thereby improving vascular permeability. Based on the combined effects of reprogramming the TME, the nanodrug improved tumor accumulation of photosensitizers and alleviated hypoxia in the TME, which facilitated the subsequent PDT. Importantly, the nanodrug regulated the immunosuppressive TME by favoring the infiltration of immunostimulatory cells over immunosuppressive cells, which potentiated the PDT-induced immune response. CONCLUSION: Our work demonstrates a sequential treatment strategy in which the combination of the CAF regulation and tumor vasculature normalization, followed by PDT, could be a promising modality for sensitizing tumor to PDT.