SLC1A5 Enhances Malignant Phenotypes Through Modulating Ferroptosis Status and Immune Microenvironment in Glioma

Abstract Glioma is the most malignant and aggressive tumor in the central nervous system with limited treatment satisfaction. Finding new therapeutic targets has still remained a major challenge. Ferroptosis is a novel and distinct type of programmed cell death, playing a regulatory role in the progression of tumors. However, the role of ferroptosis or ferroptosis-related genes (FRGs) in glioma progression has not been extensively studied. In our study, a novel ferroptosis-related prognostic model, including 7 genes, was established, in which patients were classified into the high-risk group had immuno-suppressive status and worse prognosis. Among these 7 genes, we screened SLC1A5, a FRG, as a possible new target for glioma treatment. Our results showed that the expression of SLC1A5 was significantly upregulated in glioblastoma (GBM) tissues compared with the low-grade gliomas. In addition, SLC1A5 knockdown could significantly inhibit glioma cell proliferation, invasion, and reduced the sensitivity of ferroptosis via GPX4-dependent pathway. Furthermore, SLC1A5 was found to be related to immune response and SLC1A5 knockdown decreased the infiltration and M2 polarization of tumor-associated macrophages (TAMs). Pharmacological inhibition of SLC1A5 by V9302 was confirmed to promote the efficacy of anti-PD-1 therapy. Overall, we developed a novel prognostic model for glioma based on the seven-FRGs signature, which could be applicable to glioma prognostic and immune status prediction. Besides, SLC1A5 in the model could regulate the proliferation, invasion, ferroptosis and immune state in glioma, and be applied as a prognostic biomarker and potential therapeutic target for glioma.