HLA-G functions as a tumor-intrinsic driver of growth and survival in renal cell carcinoma

作者：Ajith A, Jayaprasad AG, Chang U, Sreekumar A, Lin M, Bravo-Egana V, Mulloy LL, Horuzsko DD, Carosella ED, Horuzsko A · 发表于：Oncoimmunology · 年份：2026 · DOI：10.1080/2162402x.2026.2717680 · 研究领域：HLA-G、oncology、renal cell carcinoma、tumor immunology

HLA-G is a non-classical MHC class I molecule with potent immunoregulatory functions that is aberrantly expressed in multiple malignancies, yet its tumor-intrinsic role remains poorly defined. To characterize this potential oncogenic role of HLA-G in clear cell renal cell carcinoma (ccRCC), we utilized integrated transcriptomic, in vitro, and in vivo approaches. Analysis of the Cancer Genome Atlas (TCGA) ccRCC cohort revealed that elevated HLA-G expression was associated with immunosuppressive programs and cell populations. Interrogation of a publicly available ccRCC single-cell RNA sequencing dataset revealed that HLA-G expression within tumor epithelial clusters is associated with hypoxia-driven, metabolic transcriptional programs. Multiplex immunofluorescence of human ccRCC specimens confirmed the presence of tumor cell-intrinsic HLA-G expression in advanced disease. Functional studies using RCC7 cells expressing the full-length canonical HLA-G isoform (RCC7/HLA-G1) demonstrated increased proliferation, migration, clonogenicity, cell-cycle progression, and resistance to apoptosis compared with HLA-G-negative RCC7wt cells. RCC7/HLA-G1 xenografts exhibited accelerated tumor growth accompanied by the activation of proliferative, stemness-related, and metabolic programs. Multi-omics analyses further revealed enhanced mitochondrial activity and redox metabolic adaptation in HLA-G-expressing tumors. Mechanistically, HLA-G expression was associated with increased VEGF-C expressio...