Endothelial Metabolism in Glioblastoma Vascularity and Resistance to Immunotherapy

Glioblastoma (GBM) stands as the most prevalent and lethal primary brain tumor. Despite recent breakthroughs in immunotherapy, specifically with chimeric antigen receptor (CAR)-modified T cells, the prognosis for GBM patients remains largely unchanged. A key factor contributing to this limited progress is the unique vascular microenvironment within GBM tumors, characterized by hypoxia and abnormal angiogenesis, which hinders the efficacy of immunotherapeutic approaches due to their inaccessibility. In this study, we present evidence that the enzyme phosphoglycerate dehydrogenase (PHGDH) plays a crucial role in endothelial cell (EC) metabolism, driving the formation of a hypoxic and immune-resistant vascular microenvironment in GBM. This, in turn, leads to a diminished response to CAR-T cell immunotherapy. By conducting comprehensive metabolome and transcriptome analyses of human and mouse GBM tumors, we discovered that PHGDH expression and serine metabolism are predominantly altered in tumor ECs. We found that tumor microenvironmental cues induce activating transcription factor 4 (ATF4)-mediated PHGDH expression in ECs, initiating a redox-dependent mechanism that modulates endothelial glycolysis and results in EC overgrowth. Importantly, by genetically ablating PHGDH in ECs, we observed a reduction in excessive vasculature, alleviation of intratumoral hypoxia, and enhanced T cell infiltration within tumors. Inhibition of PHGDH also bolstered anti-tumor T cell immunity and increased the susceptibility of GBM to CAR T therapy. In conclusion, our findings indicate that targeting PHGDH to reprogram endothelial metabolism offers a novel and promising avenue for improving T cell-based immunotherapy in GBM. Further investigation of this approach may ultimately lead to better treatment options and outcomes for patients with this aggressive and difficult-to-treat malignancy.