Photothermal therapy improves the efficacy of topical immunotherapy against melanoma

•Melanoma is an aggressive cancer, and conventional treatments showed a limited therapeutic effect to advanced melanoma.•Immunotherapy is a promising approach for advanced melanoma to reverse the immunosuppressive tumor microenvironment to potentiate anti-tumor immunity.•The combination of photothermal therapy and topical imiquimod-based immunotherapy could inhibit the growth of both primary and abscopal melanoma and reversing the immunosuppressive tumor microenvironment. Melanoma is an aggressive cancer with poor response to traditional therapies. A combination of photothermal therapy and topical immunotherapy may enhance elimination of melanoma.. C57BL/6 mice with early stage and metastatic melanoma were treated with laser immunotherapy (LIT), combining near-infrared laser-based photothermal therapy (PTT) and topical imiquimod (IMQ)-based immunotherapy. The volume of primary and abscopal melanoma, animal survival, tissue temperature, transcriptome, and immune cell response were investigated to evaluate the effect of LIT. LIT could eliminate primary tumors, inhibite abscopal tumors, and prolong animal survival. The tumor tissues were selectively destroyed under a photothermal gradient between 38.2 ± 3.7 °C and 73.0 ± 2.3 °C. Gene expression analysis showed a significant increase in the expression of damage associated molecular patterns. Additionally, the population of mature dendritic cells, CD4+ T cells, and CD8+ T cells were increased, while myeloid-derived suppressor cells were downregulated after LIT. The study showed that LIT inhibited the growth of both primary and abscopal melanoma by activating systemic antitumor immune responses and reversing the immunosuppressive tumor microenvironment, making LIT a potential method for advanced melanoma treatment.