Spatial transcriptomic profiling of ultraviolet-irradiated cSCC mice

Cutaneous squamous cell carcinoma (cSCC) ranks as the second most prevalent form of nonmelanoma skin cancer, with 2.4 million cases annually worldwide and significant mortality rates. Photodynamic therapy (PDT) has shown intriguing antitumor effects and its integration with immunotherapeutic strategies has garnered increasing interest in recent years. Herein, we developed the photosensitizer STBF, a modified chlorin e6 derivative with enhanced solubility and antitumor efficacy and proposed an innovative treatment paradigm integrating PDT with anti-lymphocyte activation gene 3(LAG3) therapy to address conventional PDT limitations in advanced cSCC. Mechanically, STBF PDT induced PANoptosis, which triggers the release of damage-associated molecular patterns and mediates immunogenic cell death through the STING signaling pathway. STING agonist ADU S100 amplifies these effects and promotes dendritic cell activation. Moreover, STBF PDT reshapes the tumor microenvironment, enhancing the efficacy of immune checkpoint inhibitors. Incorporating LAG3 blockade further enhances systemic antitumor immunity in murine models of cSCC by reducing the chemotaxis and suppressive function of myeloid-derived suppressor cells while augmenting the infiltration of conventional dendritic cell and cytotoxic T lymphocyte. Our findings highlight the potential of combining PDT with immunotherapies to enhance systematic antitumor immunity, offering promising avenues for clinical intervention in metastatic cSCC and locally advanced cSCC.