HIF-responsive lncRNAs define an immunosuppressive phenotype and predict anti-angiogenic response in clear cell renal cell carcinoma

Hypothesis/Introduction Hypoxia defines clear cell renal cell carcinoma (ccRCC), but its transcriptional and therapeutic consequences are unclear. We hypothesized that a specific hypoxia-induced long noncoding RNA (lncRNA) signature links VHL–HIF signaling to immune modulation and anti-angiogenic therapy response. Materials and Methods We integrated multi-cohort transcriptomic data to prioritize hypoxia-associated lncRNAs in ccRCC. Direct regulation of candidate lncRNAs by HIF-1α was validated using ChIP-qPCR, and functional assays in RCC cell lines involving HIF-1α silencing, ectopic VHL expression, and HIF-1α overexpression. The tumor microenvironment and therapeutic vulnerabilities were analyzed using bioinformatic tools. Results We identified a five-lncRNAs signature, with AP004372.1 and AC046143.3 confirmed as direct HIF-1α transcriptional targets. This signature defined an immunosuppressive milieu with high Tregs, elevated checkpoints ( PD-1 , CTLA4 , TIGIT ), and inhibitory cytokines. These tumors also showed heightened predicted sensitivity to VEGF-targeted therapies (sunitinib, pazopanib). Conclusions Our study uncovers a hypoxia-regulated lncRNA circuit that is directly driven by HIF-1α and functionally connected to immune evasion and angiogenic dependency. This program provides a mechanistic and clinically actionable framework for stratifying ccRCC patients beyond conventional classifiers.