Chen Diyan, Wang Bo, Li Chunying, Tao Hui, Lu Fangqi, Ruan Zhijie, Zhao Zijun, Li Chunxiao, Yan Guorong, Zhang Haiyan, Liu Yeqiang, Wang Xiuli, Zhang Guolong, Zeng Qingyu
Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
Avera Medical Group Dermatology, Aberdeen, SD 57401, USA.
Cell Rep Med. 2025 Jul 15;6(7):102239. doi: 10.1016/j.xcrm.2025.102239.
Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of nonmelanoma skin cancer, with 2.4 million cases annually and significant mortality. Photodynamic therapy (PDT) is a promising antitumor strategy, and its integration with immunotherapy has garnered attention. Herein, we develop STBF, a modified chlorin e6 derivative with superior solubility and efficacy, and propose a treatment paradigm integrating PDT with immunotherapy to address conventional PDT limitations in advanced cSCC. Mechanically, STBF-PDT induces PANoptosis, triggering immunogenic cell death through the stimulator of interferon genes (STING) pathway, while the STING agonist amplifies these effects and promotes dendritic cell activation. STBF-PDT reshapes the tumor microenvironment, enhancing immune checkpoint inhibitor responses. Incorporating lymphocyte activation gene 3 (LAG3) blockade further strengthens systemic antitumor immunity by suppressing myeloid-derived suppressor cells while augmenting type 2 conventional dendritic cells, cytotoxic T lymphocytes, and tissue-resident memory T cells. Our findings highlight the potential of STBF-PDT-STING agonism-anti-LAG3 combinations for metastatic and locally advanced cSCC.
皮肤鳞状细胞癌（cSCC）是第二常见的非黑色素瘤皮肤癌形式，每年有240万例病例且死亡率颇高。光动力疗法（PDT）是一种很有前景的抗肿瘤策略，其与免疫疗法的结合已引起关注。在此，我们开发了STBF，一种具有卓越溶解性和疗效的修饰二氢卟吩e6衍生物，并提出一种将PDT与免疫疗法相结合的治疗模式，以解决晚期cSCC中传统PDT的局限性。从机制上讲，STBF-PDT诱导泛凋亡，通过干扰素基因刺激物（STING）途径触发免疫原性细胞死亡，而STING激动剂可放大这些效应并促进树突状细胞活化。STBF-PDT重塑肿瘤微环境，增强免疫检查点抑制剂反应。加入淋巴细胞活化基因3（LAG3）阻断剂可通过抑制髓源性抑制细胞，同时增加2型传统树突状细胞、细胞毒性T淋巴细胞和组织驻留记忆T细胞，进一步增强全身抗肿瘤免疫力。我们的研究结果突出了STBF-PDT-STING激动-抗LAG3联合疗法对转移性和局部晚期cSCC的潜力。
