Chen Weijia, Qiu Jingru, Li Peixia, Zhang Qianqian, Li Donghai, Li Guiling, Shan Gang
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China.
J Med Chem. 2025 Feb 13;68(3):3612-3625. doi: 10.1021/acs.jmedchem.4c02747. Epub 2025 Jan 23.
Pyroptosis, an excellent form of immunogenic cell death that can effectively activate antitumor immune responses, is attracting considerable interest as a promising approach for cancer immunotherapy. Immunogenic pyroptosis can recruit and stimulate dendritic cells to provoke further activation and tumor infiltration of T cells by releasing danger-associated molecular patterns, thus improving the tumor response to PD-1/PD-L1 checkpoint blockade immunotherapy. Here, we report the discovery of a bifunctional photosensitizer Nile Violet that can simultaneously trigger caspase-3/GSDME-mediated immunogenic pyroptosis and PD-L1 downregulation for cancer photoimmunotherapy. It was shown that this synergistic therapeutic strategy significantly inhibited tumor growth by triggering a systemic antitumor immune response. This work highlights the potential of inducing immunogenic pyroptosis and PD-L1 downregulation for synergistic tumor ablation via a single agent.
细胞焦亡是一种出色的免疫原性细胞死亡形式，能够有效激活抗肿瘤免疫反应，作为一种有前景的癌症免疫治疗方法正引起广泛关注。免疫原性细胞焦亡可通过释放危险相关分子模式招募并刺激树突状细胞，进而引发T细胞的进一步激活和肿瘤浸润，从而提高肿瘤对PD-1/PD-L1检查点阻断免疫疗法的反应。在此，我们报告了一种双功能光敏剂尼罗紫的发现，它可同时触发半胱天冬酶-3/ Gasdermin E介导的免疫原性细胞焦亡和PD-L1下调，用于癌症光免疫治疗。结果表明，这种协同治疗策略通过触发全身性抗肿瘤免疫反应显著抑制了肿瘤生长。这项工作凸显了通过单一药物诱导免疫原性细胞焦亡和PD-L1下调以实现协同肿瘤消融的潜力。
