Yu Jie, Wu Jiayan, Huang Jingsheng, Xu Cheng, Xu Mengke, Koh Clarence Zhi Han, Pu Kanyi, Zhang Yan
National Engineering Research Centre for Nanomedicine, College of Life Science and Technology, Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, PR China.
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore.
Nat Commun. 2025 Jan 2;16(1):153. doi: 10.1038/s41467-024-55529-8.
Although photodynamic immunotherapy represents a promising therapeutic approach against malignant tumors, its efficacy is often hampered by the hypoxia and immunosuppressive conditions within the tumor microenvironment (TME) following photodynamic therapy (PDT). In this study, we report the design guidelines towards efficient Type-I semiconducting polymer photosensitizer and modify the best-performing polymer into a hypoxia-tolerant polymeric photosensitizer prodrug (HTPS) for cancer photo-immunotherapy. HTPS not only performs Type-I PDT process to partially overcome the limitation of hypoxic tumors in PDT by recycling oxygen but also specifically releases a Signal Transducer and Activator of Transcription-3 (STAT3) inhibitor (Niclosamide) in response to a cancer biomarker in the TME. Consequently, HTPS inhibits the phosphorylation of STAT3, and suppresses the expression of hypoxia-inducible factor-1α. The synergistic effect results in the enhanced activation of immune cells (including mature dendritic cells, cytotoxic T cells) and production of immunostimulatory cytokines compared to Type-I PDT alone. Thus, HTPS-mediated photodynamic immunotherapy enhances tumor inhibition rate from 75.53% to 91.23%, prolongs the 100% survival from 39 days to 60 days as compared to Type-I PDT alone. This study not only provides the generic approach towards design of polymer-based Type-I photosensitizers but also uncovers effective strategies to counteract the immunosuppressive TME for enhanced photo-immunotherapy in 4T1 tumor bearing female BALB/c mice.
尽管光动力免疫疗法是一种很有前景的恶性肿瘤治疗方法，但在光动力疗法（PDT）后，肿瘤微环境（TME）中的缺氧和免疫抑制状况常常会阻碍其疗效。在本研究中，我们报告了高效I型半导体聚合物光敏剂的设计指南，并将性能最佳的聚合物改性为用于癌症光免疫治疗的耐缺氧聚合物光敏剂前药（HTPS）。HTPS不仅通过循环利用氧气进行I型PDT过程，部分克服了PDT中缺氧肿瘤的局限性，还能响应TME中的癌症生物标志物特异性释放信号转导和转录激活因子3（STAT3）抑制剂（氯硝柳胺）。因此，HTPS抑制了STAT3的磷酸化，并抑制了缺氧诱导因子-1α的表达。与单独的I型PDT相比，这种协同效应导致免疫细胞（包括成熟树突状细胞、细胞毒性T细胞）的激活增强以及免疫刺激细胞因子的产生。因此，与单独的I型PDT相比，HTPS介导的光动力免疫疗法将肿瘤抑制率从75.53%提高到91.23%，并将100%生存率从39天延长至60天。这项研究不仅提供了基于聚合物的I型光敏剂设计的通用方法，还揭示了在携带4T1肿瘤的雌性BALB/c小鼠中对抗免疫抑制性TME以增强光免疫治疗的有效策略。
