SRY介导的PD-L1上调促进肝细胞癌的免疫逃逸并造成免疫治疗反应中的性别特异性差异

Background: The impact of sex chromosomes on the tumor microenvironment (TME) is significant, beyond hormonal effects. This study investigates the role of the sex-determining gene SRY in the immune microenvironment of hepatocellular carcinoma (HCC), focusing on how SRY regulates immune checkpoints and contributes to gender disparities in immunotherapy response. Methods: Multiple HCC mouse models (chemically induced, hydrodynamic, orthotopic, subcutaneous) using SRY transgenic knockout (KO) or knock-in (KI) mice were employed. To eliminate hormonal effects, the mice were castrated. Flow cytometry, immunofluorescence, and ELISA assessed T cell changes in the TME. Cellular models used PCR array, CUT&Tag, qPCR, WB, and luciferase assays to explore SRY's transcriptional regulation. Clinical samples validated correlations between SRY, immune markers, and PD-L1. Results: •In castrated male SRY-KO mice, increased CD8 + T cells and elevated GZMB, TNF-alpha, and IFN-gamma were observed in the TME.•SRY-KI in castrated males reduced CD8 + T cells and functional markers.•Ectopic SRY in castrated females similarly impaired T cell infiltration and function.•PCR array in SRY-overexpressing HCC cells revealed upregulation of PD-L1.•CUT&Tag and luciferase assays confirmed SRY binds the IRF1 promoter, upregulating IRF1 expression.•IRF1 knockdown abolished PD-L1 upregulation, confirming an SRY-IRF1-PD-L1 axis.•In vivo, PD-L1 knockdown in SRY-overexpressing tumors reversed immune suppression and tumor growth.•Anti-PD-L1 treatment showed enhanced efficacy in SRY-overexpressing tumors.•Clinical HCC samples confirmed positive SRY-PD-L1 correlation and negative SRY-CD8 + T cell correlation. Conclusions: SRY, a male-specific gene, regulates the immune checkpoint PD-L1 via IRF1, suppressing CD8 + T cell function in the TME. Targeting the SRY-IRF1-PD-L1 axis may improve immunotherapy outcomes, especially in male HCC patients. The text has been translated and polished using AI.