代谢失调在三阴性乳腺癌（TNBC）中很突出，但针对癌症代谢的治疗策略却很有限。在这里，利用我们的 TNBC 队列 (n = 465) 的多组学数据，我们证明了糖酵解 TNBC 亚型中广泛的剪接失调和剪接体丰度增加。我们确定 SNRNP200 是葡萄糖驱动的代谢重编程的关键介质。从机制上讲，葡萄糖诱导 SNRNP200 K1610 乙酰化，防止其蛋白酶体降解。增强的 SNRNP200 有助于关键代谢酶编码基因（GAPDH、ALDOA 和 GSS）的剪接，从而增加乳酸和谷胱甘肽的产量。以 SNRNP200 为靶点的反义寡核苷酸疗法可通过激活肿瘤内 CD8 T 细胞同时抑制调节性 T 细胞来阻碍肿瘤代谢并增强抗 PD-1 疗法的疗效。临床上，较高的 SNRNP200 水平表明糖酵解 TNBC 对免疫治疗的反应较差。总体而言，我们的研究揭示了 RNA 剪接和代谢失调之间复杂的相互作用，提出了糖酵解 TNBC 免疫治疗的创新组合策略。© 2024。作者。

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.© 2024. The Author(s).