Introduction:Skin cutaneous melanoma (SKCM) is an aggressive cancer and associates with CXC chemokine receptors (CXCRs). CXCRs is a group of membrane protein involved in tumor initiation, progression, and outcome. However, the therapeutic and prognostic value of CXCRs in SKCM remained elusive. Methods: we used multiple, publicly available datasets for the analysis of CXCRs in SKCM. These datasets included GEPIA, UALCAN, TISIDB, DAVID 6.8, Metascape, GSCALite, and TIMER. Results: CXCR3 and CXCR4 were elevated in tumor samples in comparison to healthy ones. CXCR3, CXCR4, CXCR5, CXCR6, and CXCR7 were transcriptionally upregulated in the metastasis SKCM tissues compared to the primary tissues. The CXCR3, CXCR4, CXCR5, and CXCR6 were positively correlated to more prolonged overall survival (OS) at the transcriptional level. Meanwhile, CXCR3, CXCR4, and CXCR6 had an association with the stage in SKCM patients. The drug sensitivity analysis showed CXCR4 as a potential target of drug screening. The function of CXCRs and the neighboring genes mainly enriched in T cell activation, cytokine-cytokine receptor interaction, and leukocyte migration. Cancer pathway analysis showed that all the CXCRs positively affect apoptosis and EMT pathway and negative effect on the cell cycle, DNA damage response, and hormone AR pathway. Furthermore, CXCR3, CXCR4, CXCR5, and CXCR6 were positively correlated with the infiltration of lymphocytes and expression of PD-1, PD-L1, and CTLA-4. Conclusions: we found that CXCR3, CXCR4, CXCR5, and CXCR6 may provide essential clues about credible prognostic biomarkers, especially CXCR4 may be a potential target and prognostic biomarkers in the progression of SKCM.
