Zhu Wenlong, Fan Chang, Hou Yizhuo, Zhang Yanjie
Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China.
Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China.
Cancer Lett. 2025 Sep 1;627:217835. doi: 10.1016/j.canlet.2025.217835. Epub 2025 May 28.
Tumor microenvironment (TME) is a highly intricate and variable system. The Warburg effect has made researchers further realize that TME is a highly hypoxic microenvironment. Currently, it is reported that lactate is not merely a metabolic waste but also serves important biological functions, which provides a large number of reaction substrates for lactylation. Post-translational modification (PTM) is crucial for signaling and physiological regulation in both normal and cancer cells. Various PTMs play pathological roles in tumor proliferation, metabolism, and the remodeling of the tumor immunosuppressive microenvironment (TIME). Lactylation, as a newly reported PTM, plays an important role in shaping TIME and aggravating tumor immunotherapy resistance. Numerous studies have demonstrated that histone lactylation can directly stimulate gene transcription within chromatin, thereby contributing to tumor promotion and diminishing the efficacy of therapeutic agents against tumors. Advancements in multi-omics technology enable researchers to investigate lactylation-related substrates more effectively. By precisely targeting these sites, it is possible to reduce histone lactylation in order to mitigate their effects on tumor immune resistance. Despite the existence of numerous studies, there remains a notable deficiency of systematic reviews in this field. Therefore, this review focuses on the novel mechanisms of lactylation that promote tumor progression and its impact on tumor immune resistance. Finally, we propose relevant therapeutic regimens for reversing lactylation to guide tumor combined therapy, thus providing benefits upon more patients with tumor immune resistance.
肿瘤微环境（TME）是一个高度复杂且多变的系统。瓦伯格效应使研究人员进一步认识到TME是一个高度缺氧的微环境。目前有报道称，乳酸不仅是一种代谢废物，还具有重要的生物学功能，为乳酰化提供了大量反应底物。翻译后修饰（PTM）对正常细胞和癌细胞的信号传导及生理调节至关重要。各种PTM在肿瘤增殖、代谢以及肿瘤免疫抑制微环境（TIME）重塑中发挥着病理作用。乳酰化作为一种新报道的PTM，在塑造TIME和加剧肿瘤免疫治疗耐药性方面发挥着重要作用。众多研究表明，组蛋白乳酰化可直接刺激染色质内的基因转录，从而促进肿瘤生长并降低治疗药物对肿瘤的疗效。多组学技术的进步使研究人员能够更有效地研究与乳酰化相关的底物。通过精确靶向这些位点，有可能减少组蛋白乳酰化，以减轻其对肿瘤免疫抵抗的影响。尽管已有众多研究，但该领域的系统综述仍明显不足。因此，本综述聚焦于促进肿瘤进展的乳酰化新机制及其对肿瘤免疫抵抗的影响。最后，我们提出了逆转乳酰化的相关治疗方案，以指导肿瘤联合治疗，从而使更多肿瘤免疫抵抗患者受益。
