YIF1B Mutational Dysregulation Drives Cutaneous Melanoma Progression by Remodeling the TME.

YIF1B, a transmembrane protein involved in intracellular trafficking and signaling, is dysregulated in multiple cancers, but its role in SKCM remains unclear. We integrated multiomics data from cutaneous melanoma cohorts, including gene expression, DNA methylation, and somatic mutation profiles. Using the similarity network fusion (SNF) algorithm, we performed molecular subtyping based on prognosis-associated epigenetic and mutational features. Finally, the biological role of YIF1B was validated in A-375 and A-875 melanoma cell lines using qRT-PCR, wound healing, and transwell migration/invasion assays following shRNA-mediated knockdown. Patients assigned to the worst-prognosis CS5 subtype exhibited poorer survival (p < 0.05), characterized by mutation and high YIF1B expression. Mechanistically, we showed that YIF1B impairs tumor-infiltrating CD8+ T cell function. High YIF1B coupled with activation of the IL-6/JAK pathway produces a positive feedback loop in which tumor proliferation/metastasis is enhanced, as is T cell immunosuppression, eventually culminating in profound immunosuppression and tumor growth. Knockdown of YIF1B by shRNA reduced YIF1B levels in A-375 and A-875 cells, leading to suppression of cell motility and proliferation (p < 0.05). Whole-genome sequencing also revealed that activating alterations in IL-6/JAK pathway genes occur frequently in aggressive cutaneous melanoma and correlate with accelerated progression. We demonstrate that YIF1B drives cutaneous melanoma progression and enhances melanoma cell invasiveness. This function may be further enhanced in combination with activation of the IL-6/JAK pathway, suggesting an important interaction of signaling processes with immunological selection pressures. Together, YIF1B expression and IL-6/JAK pathway activation status are potential markers for SKCM prognostication and treatment guidance.