Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.

三阴性乳腺癌 (TNBC) 仍然是一个未解决的医学挑战。我们使用我们的多组学数据库（n = 465，迄今为止最大的）调查了 TNBC 的代谢失调。TNBC 样本分为三种具有不同代谢特征的基于异质代谢途径的亚型 (MPS)：MPS1，脂质代谢上调的脂肪生成亚型；MPS2，糖酵解亚型，碳水化合物和核苷酸代谢上调；和 MPS3，部分通路失调的混合亚型。这些亚型通过 72 个样本的代谢组学分析得到验证。这三种亚型具有不同的预后、分子亚型分布和基因组改变。此外，MPS1 TNBC 对靶向脂肪酸合成的代谢抑制剂更敏感，而 MPS2 TNBC 对靶向糖酵解的抑制剂表现出更高的敏感性。重要的是，抑制乳酸脱氢酶可以增强 MPS2 TNBC 中肿瘤对抗 PD-1 免疫疗法的反应。总的来说，我们的分析证明了 TNBC 的代谢异质性，并能够开发针对独特肿瘤代谢特征的个性化疗法。