Signal regulatory protein γ is associated with an exhaustion-prone immune microenvironment in metastatic melanoma.

Identifying determinants of immune microenvironment remodeling in metastatic melanoma is critical for improving prognostic assessment and therapeutic stratification. In this study, we examined the expression and clinical significance of signal regulatory protein γ (SIRPG) in skin cutaneous melanoma (SKCM) through a combination of database mining, single-cell transcriptomics, and immunohistochemical (IHC) validation. SIRPG was significantly elevated in SKCM tissues compared with normal skin, and higher expression levels were associated with prolonged overall and disease-free survival. Functional and pathway analyses revealed that SIRPG was intimately linked to immune-related processes, and correlative analyses demonstrated strong associations between SIRPG expression and both immune cell infiltration and checkpoint molecule expression, with these associations being more pronounced in metastases than in primary tumors. Single-cell RNA sequencing further localized SIRPG expression predominantly to CD8+ exhausted T cells within metastatic lesions, and multiplex immunofluorescence confirmed enriched co-expression of SIRPG and programmed cell death protein 1 (PD-1) at the protein level. Taken together, these findings implicate SIRPG in the establishment of an exhaustion-prone immunosuppressive microenvironment in metastatic melanoma and highlight its potential utility as a biomarker for disease progression and immunotherapeutic response.