Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na⁺-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na⁺/Ca²⁺ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

突变异柠檬酸脱氢酶 1 (mIDH1) 通过在各种肿瘤类型中产生致癌代谢物 R-2-羟基戊二酸 (R-2-HG) 来驱动肿瘤发生。然而，mIDH1 抑制剂似乎仅对血液肿瘤有效。实体瘤的治疗益处仍然难以捉摸，可能是由于复杂的肿瘤微环境。在这项研究中，我们发现IDH1突变肿瘤细胞产生的R-2-HG优先导入血管内皮细胞并重塑线粒体呼吸以促进肿瘤血管生成，从而赋予IDH1突变实体瘤治疗的脆弱性。从机制上讲，SLC1A1，Na ⁺在内皮细胞中优先表达的依赖性谷氨酸转运蛋白促进R-2-HG从肿瘤微环境流入内皮细胞以及R-2-HG从细胞质到线粒体的细胞内运输。R-2-HG 劫持 SLC1A1 促进线粒体 Na ⁺ /Ca ²⁺交换，激活线粒体呼吸链并促进肿瘤血管生成中的血管内皮细胞迁移。小鼠中 SLC1A1 缺陷会消除 mIDH1 促进的肿瘤血管生成以及 mIDH1 抑制剂对实体瘤的治疗效果。此外，我们报告新发现的 mIDH1 抑制剂 HH2301 在临床前模型中显示出治疗 IDH1 突变型胆管癌的良好疗效。我们共同确定了 SLC1A1 作为 R-2-HG 介导的 IDH1 突变肿瘤细胞和血管内皮细胞之间串扰的看门人的新作用，并证明了 mIDH1 抑制剂通过破坏 R 来治疗 IDH1 突变实体瘤的治疗潜力-2-HG促进肿瘤血管生成。