Profiling hypoxia signaling reveals a lncRNA signature contributing to immunosuppression in high-grade glioma.

Background: Hypoxic conditions in glioma are linked to tumor aggressiveness, poor prognosis, and treatment resistance. Long non-coding RNAs (lncRNAs) play key roles in the hypoxic and immune microenvironment of cancers, but their link to hypoxia-induced immunosuppression in high-grade glioma (HGG) is not well-studied.

Methods: Gene expression profiles from TCGA and CGGA, along with clinical and genomic data, were analyzed. Bioinformatics methods including Consensus Clustering, Pearson correlation, and Cox regression analyses were used. Cell proliferation was assessed using cell counting kit-8 and colony formation assays. Glioma-macrophage interactions were evaluated using a co-culture model.

Results: Hypoxia subtype clustering showed hypoxic stress correlates with worse HGG prognosis. Eight hypoxia-related lncRNAs (AP000695.4, OSMR-AS1, AC078883.3, RP11-545E17.3, LINC01057, LINC01503, TP73-AS1, and LINC00672) with prognostic value were identified, forming a risk signature that separated patients into distinct prognostic groups. Multivariate Cox regression confirmed the signature as an independent prognostic factor. High-risk patients had greater hypoxia, leading to an immunosuppressive environment and immunotherapy resistance via tumor-associated macrophages (TAMs). TP73-AS1 significantly influenced hypoxia-induced TAM infiltration and M2 polarization.

Conclusions: We profiled hypoxic stress in HGG and developed an 8-lncRNA hypoxia-related signature predicting patient survival and immunotherapy response, emphasizing its role in hypoxia-induced immunosuppression.