Guo Changyong, He Shipeng, Shen Huaxing, Cong Wei, Li Jinqiu, Ji Yajing, Huang Wenjing, Gao Fei, Hu Honggang
School of Medicine, Institute of Translational Medicine, Shanghai Engineering Research Center of Organ Repair, Shanghai University, Shanghai 200444, China.
Acta Pharm Sin B. 2025 Jul;15(7):3805-3818. doi: 10.1016/j.apsb.2025.05.022. Epub 2025 May 26.
Checkpoint blockade immunotherapy has emerged as a transformative approach in cancer treatment by activating tumor-infiltrating T cells. However, the efficacy of PD-L1 blockade is restricted in "cold" tumors, which are characterized by low immunogenicity, presenting a challenge to immunotherapy. This study introduces an innovative strategy, utilizing cathepsin-cleavable -(2-hydroxypropyl) methacrylamide (HPMA) polymer-assisted combined photodynamic therapy (PDT) and PD-L1 degradation for the first time, effectively treating T cell-deficient tumors. The degradable main-chain polymer, conjugated with photosensitizer porphyrin, facilitates the accumulation of reactive oxygen species (ROS), triggering immunogenic cell death (ICD) and promoting cytotoxic T lymphocytes (CTLs) infiltration into tumors. Multivalent peptide antagonists of PD-L1 promote PD-L1 degradation in lysosomes through receptor crosslinking, overcoming the adaptive cycling of PD-L1 to the tumor cell surface. These findings demonstrate that polymer-assisted PDT and PD-L1 crosslinking degradation represent a potential novel strategy for anti-tumor immunotherapy, providing valuable tools for expanding immunotherapy applications in immunosuppressive cancers.
检查点阻断免疫疗法已成为癌症治疗中的一种变革性方法，通过激活肿瘤浸润性T细胞发挥作用。然而，PD-L1阻断疗法在“冷”肿瘤中的疗效受到限制，这类肿瘤具有低免疫原性的特点，这给免疫疗法带来了挑战。本研究首次引入了一种创新策略，利用组织蛋白酶可裂解的聚（2-羟丙基）甲基丙烯酰胺（HPMA）聚合物辅助联合光动力疗法（PDT）和PD-L1降解，有效治疗T细胞缺陷型肿瘤。与光敏剂卟啉共轭的可降解主链聚合物促进活性氧（ROS）的积累，引发免疫原性细胞死亡（ICD）并促进细胞毒性T淋巴细胞（CTLs）浸润到肿瘤中。PD-L1的多价肽拮抗剂通过受体交联促进溶酶体中PD-L1的降解，克服了PD-L1向肿瘤细胞表面的适应性循环。这些发现表明，聚合物辅助的PDT和PD-L1交联降解代表了一种潜在的新型抗肿瘤免疫治疗策略，为扩大免疫疗法在免疫抑制性癌症中的应用提供了有价值的工具。
