Deciphering the tumor-suppressive role of PSMB9 in melanoma through multi-omics and single-cell transcriptome analyses

Skin cutaneous melanoma (SKCM) poses a significant challenge in skin cancers. Recent immunotherapy breakthroughs have revolutionized melanoma treamtment, yet tumor heterogeneity persists as an obstacle. Epigenetic modifications orchestrated by DNA methylation contributed to tumorigenesis, thus potentially unveiling melanoma prognosis. Here, we identified an interferon-gamma (IFN-g) sensitive subtype, which possesses favorable outcomes, robust infiltration CD8+T cells, and IFN-g score in bulk RNA-seq profile. Subsequently, we established an IFN-g sensitivity signature based on machine learning. We validated that PSMB9 is strongly correlated with immunotherapy response in both methylation and expression cohorts in this 10-probe signature. We assumed that PSMB9 acts as a putative melanoma suppressor, for its activation of CD8+T cell; capacity to modulate IFN-γ secretion; and dynamics altering IFN-g receptors in bulk tissue. We performed single-cell RNA-seq on immunotherapy patients’ tissue to uncover the nuanced role of PSMB9 in activating CD8T + cells, enhancing IFN-g, and influencing malignant cells receptors and transcriptional factors. Overexpress PSMB9 in two SKCM cell lines to mimic the hypomethylated state to approve our conjecture. Strong cell proliferation and migration inhibition were detected on both cells, indicating that PSMB9 is present in tumor cells and that high expression is detrimental to tumor growth and migration. Overall, comprehensive integrated analysis shows that PSMB9 emerges as a vital prognostic marker, acting predictive potential regarding immunotherapy in melanoma. This evidence not only reveals the multifaceted impact of PSMB9 on both malignant and immune cells but also serves as a prospective target for undergoing immunotherapeutic strategies in the future. •PSMB9 methylation is a critical prognostic indicator of response to immunotherapy in melanoma.•IFN methylation score (IMS) developed to assess the methylation status of the IFN-response.•IMS serve as a valuable tool of predicting response to ICB treatment.•Identified a distinct subtype with increased sensitivity to interferon-gamma (IFN-g).