Light-activated polymeric crosslinked nanocarriers as a checkpoint blockade immunoregulatory platform for synergistic tumor therapy

Photodynamic therapy (PDT) can enhance immune checkpoint blockade (ICB) antitumor immunity. However, PDT can significantly exacerbate the hypoxic tumor microenvironment and stimulate tumor neovascularization, promoting tumor invasion and metastasis. Camptothecin can inhibit angiogenesis by down-regulating hypoxia-inducible factor 1α (HIF-1α). Therefore, this study proposed to combine camptothecin with PDT for the first time to alleviate the disadvantage of PDT, and play its dual role of chemotherapy and antiangiogenesis. Here, a light-activated nanocarrier crosslinked the anti-PD-L1, photosensitizer, and camptothecin prodrug mildly with a thioketal bond for checkpoint blockade immunoregulation was designed. Firstly, photosensitizer-induced PDT and immunogenic cell death effect significantly increase T cell infiltration (33.3 % CD8⁺ increase), enhancing ICB antitumor immunity. Secondly, the antiangiogenic effect of camptothecin was beneficial for alleviating hypoxic tumor microenvironment exacerbated by PDT (HIF-1α expression decreased in tumor cells). Thirdly, light-activated release facilitates tumor accumulation (3.22 times) and controlled drug release. Thus, the immune checkpoint blockade combined with PDT and an antiangiogenic therapy of camptothecin creates a positive feedback co-delivery platform that exemplifies cascaded synergistic tumor therapy by checkpoint blockade immunoregulation. Besides, it also introduces a new strategy for combining small molecule drugs with macromolecules like proteins to treat various diseases.