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

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.