Modified 5‐aminolevulinic acid photodynamic therapy reduces pain and improves therapeutic effects in cutaneous squamous cell carcinoma mouse model

Abstract Background and Objectives Conventional ALA‐PDT (C‐PDT) has limited efficacy in cutaneous squamous cell carcinoma (cSCC), and there is obvious pain during treatment, which limits its clinical application. We sought to modify photodynamic therapy into a more painless and effective treatment. Methods We modified C‐PDT by reducing the incubation time of the pro‐sensitizer and increasing the light dose; we named this method modified ALA‐PDT (M‐PDT). We compared the pain response and curative effect between C‐PDT and M‐PDT in cSCC mouse models. Pain‐related proteins were examined by western blot analysis and immunohistochemistry. Tumor progression‐associated signaling pathways were analyzed by RNA‐seq and western blot analysis. Reactive oxygen species (ROS) generation was measured with a ROS test kit and Microplate reader. Results M‐PDT greatly reduced pain during treatment. Interestingly, when the cSCC tumor volume increased to 150–200 mm 3 , M‐PDT almost completely eliminated the tumors, while C‐PDT did not. The better curative effect of M‐PDT might be due to the stronger suppression of the Stat3, Erk1/2, and mTOR signaling pathways. Moreover, flow cytometry demonstrated that M‐PDT could recruit CD8 + T cells to inhibit cSCC progression. Further investigation determined that the different mechanisms of C‐PDT and M‐PDT were related to more ROS generation induced by M‐PDT. Conclusions Our results suggest that M‐PDT, which is more painless and effective than C‐PDT, is expected to provide a solution for the treatment of cSCC.