CD27 expression is a clinically accessible biomarker for predicting immunotherapy response in melanoma.

Immunotherapy has transformed melanoma treatment, yet only a subset of patients benefit and clinically effective biomarkers remain limited. Here, we report a comprehensive analysis evaluating CD27 as a predictive and prognostic biomarker in melanoma across public datasets and a clinical cohort. Public transcriptomic datasets revealed that high CD27 mRNA expression correlates with immune checkpoint genes, enhanced immune infiltration, and favorable prognosis. In advanced melanoma patients treated with immune checkpoint inhibitors, CD27 demonstrated strong predictive performance based on receiver operating characteristic (ROC) curve analysis, with AUC values of 0.763 (PRJEB23709, n = 91) and 0.659 (GSE91061, n = 51). These findings were validated in a retrospective melanoma cohort (n = 102) from the First Affiliated Hospital of Zhengzhou University. CD27 mRNA levels measured by qRT-PCR achieved an AUC of 0.688, and protein levels assessed by immunohistochemistry yielded an AUC of 0.656, both surpassing PD-L1 (AUC = 0.460). Notably, CD27 IHC showed 69.8% sensitivity compared to 27.9% for PD-L1 in identifying responders. Patients with CD27-positive tumors exhibited significantly longer progression-free survival. Multiplex immunofluorescence confirmed CD27 expression in CD45RO⁺ memory T cells, highlighting its role in mediating anti-tumor immunity. These results establish CD27 as a clinically actionable biomarker with superior predictive value over PD-L1 for melanoma immunotherapy response.