Lactate-driven lysine lactylation in tumor progression, therapy resistance, and prognosis

Lactylation is a post-translational modification (PTM) of proteins involved in epigenetic regulation. The large amounts of lactate produced in tumors via the Warburg effect drive lysine lactylation. Lysine lactylation is a key link between the Warburg effect and the malignant phenotype of cancer that enables tumors to adapt to their microenvironment and resist therapeutic interventions through regulating gene expression and metabolism [1]. In a seminal study, Chen et al. [2] demonstrated that a large amount of the lactate produced becomes an “accomplice” of tumor cells during tumor cell metabolism, helping them to evade the killing effect of radiotherapy and chemotherapy in the journal Nature. And they found that lactate is primarily involved in DNA repair mediated by homologous recombination (HR). Specifically, the protein that responds to DNA damage, Nijmegen breakage syndrome 1 (NBS1), can be lactylated at lysine 388 (K388) under the action of the TIP60 protein, promoting the formation of an efficient meiotic recombination 11 (MRE11)–RAD50–NBS1 complex (MRN complex) and the accumulation of HR repair proteins at the sites of DNA double-strand breaks. This process allows tumor cells to resist radiotherapy and chemotherapy. Interestingly, Chen et al. [3] reported that when DNA is damaged in tumor cells, ataxia-telangiectasia mutated (ATM) protein kinase phosphorylates acetyltransferase CREB binding protein (CBP). Subsequently, the phosphorylated CBP activates the lactylation of the HR protein MRE11 at lysine 673 (K673), strengthening the function of the DNA repair complex MRN to promote DNA end resection and HR repair, leading to chemoresistance. In contrast, inhibiting CBP or using lactate dehydrogenase (LDH) inhibitors can downregulate the lactylation of MRE11, disrupt HR repair, and enhance the sensitivity of tumor cells to chemotherapy. This evidence innovatively found that lactylation modification can promote HR and DNA repair, ultimately leading to radiation and chemotherapy resistance in tumor cells. The detailed molecular mechanism of lactylation on the HR repair of DNA is shown in Fig. 1.

Numerous studies have found that lactate and lactylation levels can influence the occurrence and development of tumors. It is well known that tumor cells produce lactate primarily due to the Warburg effect, which favors glycolysis and fermentation processes for energy acquisition. This metabolic shift ultimately results in the accumulation of lactate. Moreover, lactate from the high glycolysis can be a substrate for lactylation in tumor cells. Conversely, lactylation can also regulate glycolytic enzymes to promote glycolysis in tumor cells. For instance, Li et al. [4] found that lactate dehydrogenase A (LDHA) activated by TTK protein kinase can catalyze lactate production and promote histone lactylation, thereby forming a positive feedback loop to help tumor cells to store energy. In addition, lactylation can induce tumor angiogenesis. Luo et al. [5] showed that the lactylation of hypoxia-inducible factor 1α (HIF1α) can upregulate the transcriptional levels of hyaluronic acid (HA) binding protein KIAA1199, promote the proliferation of endothelial cells and increase tumor vessel density, thereby providing the nutrients and oxygen required for tumor growth and metastasis. Hong et al. [6] found that lactylation plays a potential role in the diagnosis of hepatocellular carcinoma. Specific levels of lysine lactylation in different tissues may serve as potential diagnostic markers for differentiating primary from metastatic lesions in hepatocellular carcinoma. Therefore, lactate and lactylation play important roles in the occurrence and development of tumors, and the level of lactylation of some key proteins can be used as a potential diagnostic marker for tumors, such as hepatocellular carcinoma.

Lactylation in tumor cells is also involved in resistance to radiotherapy and chemotherapy and thus serves as a potential prognostic indicator for cancer patients. It is well known that radiotherapy and chemotherapy can induce DNA damage to inhibit tumor cell proliferation [2,7]. However, abundant studies have shown that lactylation can promote DNA repair in tumor cells, leading to resistance to radiotherapy and chemotherapy. For instance, Li et al. [8] found that lactate accumulation in glioblastoma stem cells can promote the lactylation of the DNA repair protein X ray cross complementing protein 1 (XRCC1) to enhance DNA damage repair, thereby generating resistance to radiotherapy and chemotherapy. Chen et al. revealed that the lactylation of both MRE11 and NBS1 influences HR and DNA repair in tumor cells and further determines chemotherapy resistance [2,3]. Significantly, Chen et al. [2] discovered that reducing lactate production using the LDHA inhibitor stiripentol inhibited NBS1 K388 lactylation and decreased DNA repair efficacy to enhance the synergistic anticancer effect of combination of radiotherapy and chemotherapy. Therefore, targeted lactylation inhibition may reduce the ability of tumor cells to repair DNA and enhance the efficacy of radiotherapy and chemotherapy. In addition, lactylation is an emerging as a prognostic indicator in patients with tumors. Hong et al. [6] found that high lactylation levels are associated with poor prognosis in hepatocellular carcinoma patients, while low levels correlate with a better outcome. Yang et al. [9] found that protein lactylation at lysine 28 (K28) of adenylate kinase 2 (AK2) promotes the metastasis of hepatocellular carcinoma cells, thereby aggravating the progression of hepatocellular carcinoma. Chao et al. [10] found that high levels of histone H3K18 lactylation are associated with poor prognosis in epithelial ovarian cancer. Overall, these findings collectively suggest that lactylation is a new target for tumor treatment and a marker for evaluating cancer prognosis, providing a strategy for precision treatment.

The characteristics of lactylation differ from those of other post-translational modifications such as histone acetylation and methylation. Lactylation relies on lactate from tumor glycolysis, is enriched in the hypoxic core of tumors, and preferentially regulates glycolysis-related metabolic genes, for example, modifying H3K18la to boost glycolytic enzyme expression [11,12]. Histone lactylation acts as a “metabolic sensor” that directly links tumor glycolysis to gene expression [13]. This sensing function is distinct from that of other lysine modifications such as acetylation, which is normally associated with proliferation, and methylation, which is typically linked to differentiation [14,15]. In summary, the unique characteristics and function of lactylation as a metabolic sensor offer considerable clinical potential for tumor intervention.

Although lactylation and tumors have been extensively studied, several unresolved challenges remain. The future research directions in this field remain unclear. The technical hurdles in lactylation research include the incompletely clarified specificity and efficiency of lactylation, the ongoing debate on the primary enzymes required for adding and removing lactyl groups, and assays frequently involving conditions that fail to accurately reflect in vivo environments [16]. The specificity of the current intervention strategies involving lactylation inhibitors is low, as most only broadly inhibit lactyltransferase activity without targeting specific proteins or modification sites, preventing protumor lactylation from being distinguished from physiologically essential lactylation [17]. Additionally, off-target risks persist in these intervention strategies: some lactylation inhibitors may cross-react with other acylation pathways such as acetylation and propionylation or disrupt normal lactate metabolism, thereby causing unintended cytotoxicity [18]. Future studies on lactylation should focus on several aspects to address these issues. High-resolution structural biology techniques can be used to clarify the binding modes of lactyltransferases/delactylases to substrates. Highly specific detection tools such as single-domain antibodies could be developed for precisely localizing low-abundance sites in tissues. Finally, site-specific inhibitors could be designed to reduce the off-target effects, laying the foundation for clinical translation.

In this commentary, we summarize recent breakthroughs elucidating the mechanism of lactylation in promoting DNA repair and therapy resistance, discuss its broader role in tumor progression, and evaluate its potential as a diagnostic and prognostic biomarker. In addition to serving as a biomarker, the clinical translational potential of targeted lactylation warrants further attention. Researchers should focus on reversing tumor treatment resistance through interfering with the lactylation process and disrupting the DNA repair mechanism mediated by lactylation, offering a novel therapeutic strategy to increase the efficacy of current antitumor treatments. Key prospects for future research involve exploring the crosstalk between lactylation and other post-translational modifications in tumor biology, developing highly specific lactylation inhibitors, and validating the translational value of lactylation-targeted therapies in large-scale clinical trials. Targeted drugs developed based on enzyme of lactylation hold the potential to facilitate personalized treatment strategies. Therefore, although many studies have been conducted on lactylation and tumors, new directions must be explored in lactylation research to provide new perspectives on tumor treatment and prognosis.

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