Immune checkpoint blockade (ICB) is a powerful oncologic treatment modality for a wide variety of human
malignancies, but the patient response rate to this treatment remains low, especially in patients with cutaneous
squamous cell carcinoma (cSCC). 5-Aminoleuvulinic
acid-
photodynamic therapy (ALA-
PDT) is widely used to treat cancerous and precancerous
skin diseases, but the value of ALA-
PDT in the treatment of invasive cSCC is debatable. Our previous studies have shown that ALA-
PDT can induce antitumor immune responses by promoting the immunogenic death of
tumor cells. However, it is unclear whether ALA-
PDT exerts synergistic effects with ICB in cSCC. Here, we report that PD-L1 blockade potentiates the antitumor effects of ALA-
PDT both on primary and distant
tumors, and optimizes the tumor microenvironment in cSCC. In this study, we first detected PD-L1 expression in patients with different grades of cSCC. Then we found the combination of anti-PD-L1
monoclonal antibody (mAb) and ALA-
PDT killed
tumor cells by apoptosis- and/or ferroptosis-mediated immunogenic cell death (ICD) and stimulated systemic immune response, as well as building the immunological memory response to prevent
tumor recurrence. Furthermore, we found that combination
therapy can be used to recruit
tertiary lymphoid structure (TLS)-like intratumoral lymphoid aggregates, which may promote tumor-infiltrating lymphocyte (TIL)-mediated antitumor immunity. In summary, our work demonstrates that ICB treatment with an anti-PD-L1 antibody is a promising strategy that may potentiate the antitumor effects of ALA-
PDT in cSCC.