Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)–mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti–PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti–PD-1 immunotherapy.

中文翻译：

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二磷酸鸟苷-甘露糖抑制三阴性乳腺癌的同源重组修复并增强抗肿瘤免疫力


三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，预后较差。具有高同源重组缺陷（HRD）评分的 TNBC 受益于 DNA 损伤剂，包括铂类药物和聚（ADP-核糖）聚合酶（PARP）抑制剂，而那些具有低 HRD 评分的 TNBC 仍然缺乏治疗选择。因此，我们试图利用代谢改变来诱导 HRD 并使 HRD 评分较低的 TNBC 中的 DNA 损伤剂敏感。我们系统地分析了 TNBC 代谢组学，并鉴定了一种阻碍同源重组修复 (HRR) 的代谢物二磷酸鸟苷 (GDP)-甘露糖 (GDP-M)。从机制上讲，上游酶GDP-甘露糖焦磷酸化酶-A (GMPPA) 的低表达导致 TNBC 中 GDP-M 的内源性上调。肿瘤细胞中GDP-M的积累进一步减少了乳腺癌易感基因2（BRCA2）与泛素特异性肽酶21（USP21）之间的相互作用，从而促进泛素介导的BRCA2降解，从而抑制HRR。在治疗上，我们证明补充 GDP-M 可以使 DNA 损伤剂敏感，从而在体外（癌细胞系和患者来源的类器官）和体内（免疫缺陷小鼠的异种移植物）模型中损害肿瘤生长。此外，GDP-M 与 DNA 损伤剂的组合在免疫功能正常的同系小鼠模型中激活了 STING 依赖性抗肿瘤免疫。因此，GDP-M 补充与 PARP 抑制相结合增强了抗 PD-1 抗体的功效。总之，这些发现表明 GDP-M 是一种重要的 HRD 相关代谢物，并为 HRD 评分较低的 TNBC 提出了一种有前景的治疗策略，即结合 GDP-M、PARP 抑制剂和抗 PD-1 免疫疗法。