Interleukin-30 promotes melanoma spreading and triggers LAG-3 expression and T cell exhaustion.

Melanoma is an aggressive and highly metastatic malignancy with significant mortality. Although immune checkpoint inhibitors have improved outcomes in advanced disease, immune resistance remains a critical barrier to durable responses, emphasizing the need to define the molecular mechanisms underlying therapeutic failure. Interleukin (IL)30 has been identified as a cancer progression driver with immunosuppressive function in the tumour-microenvironment. Whether it is involved in melanoma aggressiveness and metastasis is unknown. Immunopathological studies, RNA-Seq and CIBERSORTx analyses of tissue samples from the TCGA-SKCM patient cohort, reveal that IL30 expression is absent in normal skin, while it can be found in melanoma and infiltrating immune cells, mostly macrophages. The putative IL30 receptor complex, IL-6Rα/gp130, is expressed by melanoma cells, which respond to IL30 stimulation with increased proliferation and migration, consistent with IL30-mediated upregulation of metastasis-associated genes, including ANG2, CXCR4, ITGB1, MMP2, NME, SNAI2, VEGFA, VEGFC, and L1CAM. Bioinformatic analysis of IL30 transcript levels in TCGA-SKCM tissue specimens, reveals increased IL30 expression in metastases compared with primary tumors, corroborating the experimental findings at the translational level. IL30 reprograms the melanoma immunophenotype by inducing multiple immune checkpoint molecules, including LSECtin, LGALS3, LGALS9, LAG-3, TIM-3, B7-H4, B7-H3, VISTA, and PD-1. Concurrently, IL30 suppresses T cell function by reducing CD25 and HLA-DR expression on CD4⁺ and CD8⁺ T cells, inhibiting their activation and proliferation, decreasing TNF-α and IFN-γ production, and boosting LAG-3 expression, which strongly correlates with IL30 levels in clinical samples. Collectively, these findings identify IL30 as a critical driver of melanoma dissemination and T cell exhaustion, providing a mechanistic link to immune resistance and failure of combination immunotherapies.