Targeting LAG3 to alter the tumor immune reactivity of CD8+T cells is a potential therapy for skin cutaneous melanoma.

CD8+ T cells exert a significant effect in immune infiltration, drug resistance and cell survival in cancers, but the roles and mechanisms in skin cutaneous melanoma (SKCM) remain unclear. In the present study, prognostic biomarkers associated with CD8+ T cell subsets were screened, and the significance of CD8+ T cells in SKCM immunotherapy was explored by integrated single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk RNA-seq) analyses. Based on scRNA-seq analysis, CD8 + T cells were divided into two subgroups: CD8 + LAG3 + T cells and CD8 + LAG3-T cells. Cell-cell communication analysis revealed that both subsets closely interact with melanoma cells. Differential gene expression analysis showed that LAG3 was up-regulated in SKCM, and immune infiltration analysis showed that the survival prognosis was significantly better in the Score-High group than in the Score-Low group. Assay results demonstrated that both the LAG3 inhibitor ZYF0033 and the monoclonal antibody Miptenalimab significantly suppressed tumor proliferation and metastasis, while enhancing immune cell infiltration in murine models. This study revealed the functional heterogeneity of CD8 + T cells in SKCM and demonstrated that LAG3 inhibition suppresses tumor proliferation and metastasis. Moreover, reduced LAG3 expression significantly enhanced CD8 + T cell immune infiltration, highlighting the regulatory role of LAG3 in CD8 + T cell function within the tumor microenvironment. These findings provided further evidence that SKCM may be effectively treated by targeting LAG3.