癌症光动力疗法（PDT）的失败很大程度上归因于过多的基质和有缺陷的脉管系统，限制了肿瘤中光敏剂的渗透和氧灌注。在这项研究中，一种将癌症相关成纤维细胞（CAF）调节与肿瘤血管结合起来的纳米药物标准化是为了连续地使 PDT 敏感而定制的。该纳米药物对CAF表现出高度靶向性，并有效地将激活的CAF逆转为静止状态，从而减少肿瘤微环境（TME）中的胶原蛋白沉积，从而克服了保护性物理屏障。此外，纳米药物调节血管内皮细胞并恢复肿瘤血管系统，从而改善血管通透性。基于对TME进行重编程的综合作用，纳米药物改善了肿瘤光敏剂的积累并缓解了TME中的缺氧，从而有利于随后的PDT。重要的是，纳米药物通过有利于免疫刺激细胞而不是免疫抑制细胞的浸润来调节免疫抑制性TME，从而增强PDT诱导的免疫反应。我们的工作展示了一种序贯治疗策略，其中CAF调节和肿瘤脉管系统正常化相结合，然后是PDT 可能是一种有前途的使肿瘤对 PDT 敏感的方式。© 2023 Fei 等人。

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.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.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.© 2023 Fei et al.