HSPA5-mediated glioma hypoxia tolerance promotes M2 macrophage polarization under hypoxic microenvironment

•The hypoxic microenvironment and immune microenvironment of gliomas play a crucial role in tumor progression.•Targeting the hypoxic microenvironment and immune microenvironment of gliomas offers a promising therapeutic strategy.•HSPA5 facilitates the development of an immunosuppressive microenvironment by enhancing hypoxia tolerance in gliomas.•Silencing HSPA5 alleviated glioma hypoxia tolerance and induced the polarization of tumor-associated macrophages (TAMs) toward the M1 phenotype. The induced macrophages could exhibit a tumor-suppressive effect. The tumor microenvironment (TME), with hallmark features of hypoxia and immunosuppression, plays a crucial role in the progression of various solid tumors. However, the intricate interplay between tumor hypoxia and the formation of tumor immune microenvironment in glioma remains incompletely understood. In the present study, we initially identified genes associated with tumor hypoxia and the immune microenvironment through GSEA and IMMPORT database analysis. We subsequently identified hypoxia- and immune-related genes associated with glioma prognosis through further cross-analysis and multidatabase integrated analysis. HSPA5 was ultimately identified as a potential target gene related to the formation of the hypoxic microenvironment and immune microenvironment in glioma. Furthermore, we conducted MTT, colony formation, EdU, migration and invasion assays and intracranial orthotopic tumor model analysis to further evaluate the impact of interfering with HSPA5 expression on the hypoxic and immune microenvironments of glioma. We found that HSPA5 is highly expressed in glioma cells and tissues and is associated with a poor prognosis. Further investigation revealed that hypoxia promotes the malignant biological characteristics of glioma and reshaping the Immunosuppressive phenotype of tumor-associated macrophages (TAMs) through upregulation of the HIF-1α/HSPA5 axis. Silencing HSPA5 alleviated glioma hypoxia tolerance and induced the polarization of TAMs toward the M1 phenotype. The induced macrophages could exhibit a tumor-suppressive effect. These observations suggest that HSPA5 upregulation promotes glioma progression by inducing hypoxia tolerance and reshaping the Immunosuppressive phenotype of TAMs. Therefore, targeting HSPA5 may be a novel therapeutic strategy for glioma.