靶向NAT1-ENO1-乳酸轴可 destabilize PD-L1，从而重振结直肠癌的抗肿瘤免疫
Targeting the NAT1-ENO1-Lactate Axis Destabilizes PD-L1 to Reinvigorate Antitumor Immunity in Colorectal Cancer.
摘要(中文译文)
代谢失调是肿瘤发生的标志性特征，并深刻影响免疫监视；然而，在结直肠癌（CRC）中，其潜在机制和靶向治疗仍然有限。在此，我们利用公共数据库、小鼠模型和多组学分析，鉴定出N-乙酰转移酶1（NAT1）是一个关键的预后相关基因，并作为CRC中肿瘤免疫的重要调节因子。我们证明NAT1抑制糖酵解和乳酸产生，从而促进免疫激活的肿瘤微环境（TME）。在机制上，NAT1与关键糖酵解酶烯醇化酶1（ENO1）相互作用，在赖氨酸343（K343）位点对其乙酰化，从而抑制其活性。然而，肿瘤细胞中NAT1的缺失导致ENO1激活增强，进而驱动糖酵解和乳酸产生。随后乳酸与TNF受体相关因子6（TRAF6）结合，促进其寡聚化和激活，导致PD-L1的K63连接泛素化，从而增强PD-L1稳定性并促进免疫逃逸。重要的是，NAT1低表达的CRC患者肿瘤对抗PD-1治疗表现出更高的敏感性，而NAT1缺失在临床前小鼠模型中显著提高了抗PD-L1抗体治疗的疗效。总之，我们的发现强调了NAT1在重塑TME中的关键作用，并提示靶向NAT1-ENO1-乳酸轴是增强CRC免疫治疗的一种有前景的治疗策略。
Abstract
Metabolic dysregulation is a hallmark of tumorigenesis and profoundly impacts immune surveillance; however, the underlying mechanisms and targeted treatments remain limited in colorectal cancer (CRC). Here, we utilize public databases, mouse models, and multi-omics analyses to identify -acetyltransferase 1 (NAT1) as a critical prognostic-associated gene that emerges as a significant modulator of tumor immunity in CRC. We demonstrate that NAT1 suppresses glycolysis and lactate production, thereby promoting an immune-activated tumor microenvironment (TME). Mechanistically, NAT1 interacts with enolase 1 (ENO1), a key glycolytic enzyme, acetylating it at lysine 343 (K343) and thereby inhibiting its activity. However, loss of NAT1 in tumor cells leads to enhanced ENO1 activation, which in turn drives glycolysis and lactate production. Lactate then binds to TNF receptor-associated factor 6 (TRAF6), promoting its oligomerization and activation, leading to K63-linked ubiquitination of PD-L1, which enhances PD-L1 stability and facilitates immune evasion. Importantly, low NAT1-expressing tumors from CRC patients show increased sensitivity to anti-PD-1 therapy, and NAT1 deficiency significantly improves the efficacy of anti-PD-L1 antibody treatment in preclinical mouse models. Collectively, our findings highlight the critical role of NAT1 in reshaping the TME and suggest that targeting the NAT1-ENO1-lactate axis represents a promising therapeutic strategy to enhance immunotherapy in CRC.
如何引用
AMA
Yi-Xuan Liu, Wen-Xin Wu, Yang Zang, Guang Hu, Xin Guo, Yi Wang, et al. Targeting the NAT1-ENO1-Lactate Axis Destabilizes PD-L1 to Reinvigorate Antitumor Immunity in Colorectal Cancer.. MedComm. 2026; doi:10.1002/mco2.70867.
APA
Yi-Xuan Liu, Wen-Xin Wu, Yang Zang, Guang Hu, Xin Guo, Yi Wang, et al (2026). Targeting the NAT1-ENO1-Lactate Axis Destabilizes PD-L1 to Reinvigorate Antitumor Immunity in Colorectal Cancer.. MedComm. https://doi.org/10.1002/mco2.70867
GB/T 7714
Yi-Xuan Liu, Wen-Xin Wu, Yang Zang, Guang Hu, Xin Guo, Yi Wang, et al. Targeting the NAT1-ENO1-Lactate Axis Destabilizes PD-L1 to Reinvigorate Antitumor Immunity in Colorectal Cancer.[J]. MedComm, 2026 doi:10.1002/mco2.70867.
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