BackgroundSkin cutaneous melanoma (SKCM) is the most threatening type of skin cancer. Approximately 55,000 people lose their lives every year due to SKCM, illustrating that it seriously threatens human life and health. Homeodomain-only protein homeobox (HOPX) is the smallest member of the homeodomain family and is widely expressed in a variety of tissues. HOPX is involved in regulating the homeostasis of hematopoietic stem cells and is closely related to the development of tumors such as breast cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. However, its function in SKCM is unclear, and further studies are needed.MethodsWe used the R language to construct ROC (Receiver-Operating Characteristic) curves, KM (Kaplan‒Meier) curves and nomograms based on databases such as the TCGA and GEO to analyze the diagnostic and prognostic value of HOPX in SKCM patients. Enrichment analysis, immune scoring, GSVA (Gene Set Variation Analysis), and single-cell sequencing were used to verify the association between HOPX expression and immune infiltration. In vitro experiments were performed using A375 cells for phenotypic validation. Transcriptome sequencing was performed to further analyze HOPX gene-related genes and their signaling pathways.ResultsCompared to normal cells, SKCM cells had low HOPX expression (p< 0.001). Patients with high HOPX expression had a better prognosis (p< 0.01), and the marker had good diagnostic efficacy (AUC = 0.744). GO/KEGG (Gene Ontology/ Kyoto Encyclopedia of Genes and Genomes) analysis, GSVA and single-cell sequencing analysis showed that HOPX expression is associated with immune processes and high enrichment of T cells and could serve as an immune checkpoint in SKCM. Furthermore, cellular assays verified that HOPX inhibits the proliferation, migration and invasion of A375 cells and promotes apoptosis and S-phase arrest. Interestingly, tumor drug sensitivity analysis revealed that HOPX also plays an important role in reducing clinical drug resistance.ConclusionThese findings suggest that HOPX is a blocker of SKCM progression that inhibits the proliferation of SKCM cells and promotes apoptosis. Furthermore, it may be a new diagnostic and prognostic indicator and a novel target for immunotherapy in SKCM patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12935-023-02962-2.