Ce6 derivative photodynamic therapy triggers PANoptosis and enhances antitumor immunity with LAG3 blockade in cutaneous squamous cell carcinoma

  • Cell Rep Med. 2025 Jul 15;6(7):102239. doi: 10.1016/j.xcrm.2025.102239.
Diyan Chen  1 ,  Bo Wang  2 ,  Chunying Li  1 ,  Hui Tao  1 ,  Fangqi Lu  1 ,  Zhijie Ruan  1 ,  Zijun Zhao  1 ,  Chunxiao Li  1 ,  Guorong Yan  1 ,  Haiyan Zhang  1 ,  Yeqiang Liu  1 ,  Xiuli Wang  3 ,  Guolong Zhang  4 ,  Qingyu Zeng  5
Affiliations
  • 1. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 2. Avera Medical Group Dermatology, Aberdeen, SD 57401, USA.
  • 3. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
  • 4. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
  • 5. Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: [email protected].
PMID: 40669448 DOI: 10.1016/j.xcrm.2025.102239
Abstract

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.

Keywords
ADU-S100; LAG3; PANoptosis; cSCC; photodynamic therapy.
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