Targeting the Metabolic-Immune Regulator SLC35F6 Enhances Temozolomide and Anti-PD-L1 Therapy in Glioma.

Abstract

Single-pathway targeted therapy is often insufficient to control malignant glioma progression, and the blood-brain barrier (BBB) remains a major obstacle to effective drug delivery. Therefore, discovering multifunctional target molecules and corresponding drugs that can penetrate the BBB can provide new strategies for targeted glioma therapy. Analysis of public databases and 179 clinical samples showed that solute carrier family 35 member F6 (SLC35F6) was upregulated in gliomas and associated with poorer clinical outcomes. Proteomic analyses and functional validation identified PIK3R2 as a potential downstream mediator of SLC35F6. Mechanistically, SLC35F6 knockdown reduced the abundance of the p85β-p110β complex and promoted proteasome-dependent degradation of p85β (encoded by PIK3R2). These findings support a model in which SLC35F6 maintains p85β stability, at least in part, by preserving the p85β-p110β association, with PIK3R2-associated PI3K/AKT signaling contributing to aerobic glycolysis, glioma cell proliferation, and reduced sensitivity to temozolomide (TMZ). In parallel, SLC35F6 promoted macrophage polarization toward the M2-like phenotype, with evidence supporting the involvement of the macrophage migration inhibitory factor (MIF)/CD74 axis, thereby contributing to an immunosuppressive tumor microenvironment. Leveraging these mechanisms, we developed a dual-ligand nanoplatform designed to facilitate trans-BBB delivery of siSLC35F6, TMZ, and an anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody (α-PD-L1). SLC35F6 knockdown suppressed glycolytic reprogramming and induced changes in macrophage polarization consistent with a less immunosuppressive immune microenvironment, thereby enhancing glioma sensitivity to both TMZ and α-PD-L1. Collectively, this study identifies SLC35F6 as a potential therapeutic target for glioma and provides a rationale for further preclinical development of BBB-crossing combinatorial therapeutic approaches.