Lactate: A Key Promoter of Cancer Stem Cells and Implications for Cancer Therapy

A groundbreaking study published in Cell Metabolism reveals how lactate promotes cancer stemness and therapy resistance by reshaping epigenetic landscapes [1]. By employing advanced single-cell tracking and machine learning in tumor organoids, the authors demonstrate that lactate suppresses differentiation and induces dedifferentiation of cancer cells into stem-like states through MYC activation. This discovery underscores lactate as a key regulator of tumor dynamics and identifies bromodomain protein 4 (BRD4) inhibitors as a promising therapeutic strategy to prevent relapse. Tumor cells typically rely on glycolysis (the Warburg effect) for rapid energy supply, producing a large amount of lactate. Traditionally viewed as a metabolic byproduct, lactate is now recognized as a signaling molecule with multiple roles in the tumor microenvironment. The accumulation of lactate is closely associated with tumor proliferation, invasion, and drug resistance [2]. In gastric cancer, lactate promotes NBS1 K388 lactylation, enhancing MRN complex formation and recruitment to DNA double-strand breaks, thereby improving homologous recombination repair and mediating chemoradiotherapy resistance [3]. Lactate metabolism has thus emerged as a key focus in cancer research. Cancer recurrence and metastasis remain major clinical challenges, driven largely by cancer stem cells (CSCs). CSCs exhibit self-renewal, multi-directional differentiation, and drug resistance, enabling survival post-therapy and tumor regeneration. Cancer differentiated cells (CDCs), as an important component of the tumor cell population, exhibit significant functional differences from CSCs. Research by the Rodríguez Colman team at the University Medical Center Utrecht revealed that murine intestinal stem cells and differentiated cells display distinct metabolic profiles and interact via lactate [4]. This suggests similar metabolic heterogeneity may exist between CSCs and CDCs in human intestinal tumors, with lactate playing a potential role in tumor progression. Further investigation into lactate's functional impact in these interactions is warranted. Immunostaining of clinical samples showed that the expression level of monocarboxylate transporter 4 (MCT4), a lactate transporter, was significantly higher in CDCs than in CSCs. This indicates that CDCs have a higher glycolysis level. This finding demonstrates that, although tumor metabolism is generally characterized by the Warburg effect, there are notable differences in aerobic glycolysis levels among different tumor cell populations. Single-cell analysis further confirmed that the lactate level was elevated in CDCs relative to CSCs, indicating a higher glycolytic rate in CDCs. However, no significant differences were observed in basal glucose levels or glucose uptake between CDCs and CSCs. Interestingly, CSCs exhibited a greater capacity for lactate uptake compared to CDCs. Based on these observations, the researchers propose that lactate produced and released by CDCs is absorbed by CSCs, representing a metabolic interaction between the two cell types. In summary, CDCs display a higher glycolytic activity than CSCs. Based on these metabolic differences, researchers further explored the impact of lactate. To further investigate the metabolic differences between CSCs and CDCs, as well as their interactions, Rodríguez Colman's team developed a human organoid model. They implanted a stem cell reporter (STAR) and three metabolite sensors (reporting NAD+/NADH, glucose, and lactate, respectively). The analysis yielded surprising results: high lactate concentrations increased the CSC population. To elucidate the mechanism underlying this phenomenon, the researchers conducted 4D imaging of tumor organoid development. The results revealed that, under control conditions, the proportion of stem cells in organoid tissues decreased over time due to cell differentiation, with 36% of all cells differentiating and less than 1% undergoing dedifferentiation. In contrast, under lactate treatment, cell differentiation decreased by 50%, and 27% of cells dedifferentiated. These findings demonstrate that lactate-induced increases in CSCs result from the inhibition of CSC differentiation and the induction of CDC dedifferentiation into the CSC state. To further explore how lactate inhibits CSC differentiation and promotes CDC dedifferentiation, the researchers investigated the division patterns of intestinal stem cells. Typically, after intestinal stem cells divide, they produce two daughter cells with the same fate—either both differentiated cells or both stem cells. Only 4.42% of stem cell divisions result in one differentiated cell and one stem cell. However, lactate treatment disrupted this balance, increasing the frequency of asymmetric division to 18.3%, a more than threefold rise. Notably, this increase in asymmetric division was primarily driven by the dedifferentiation of one of the two differentiated cells, transitioning from a CDC to a CSC. In summary, lactate increases the CSC population within tumors by converting CDCs into CSCs. The key mechanism underlying this process is lactate's ability to remodel CDC metabolism and induce stemness. To further investigate the mechanism underlying this dedifferentiation phenomenon, Rodríguez Colman's team conducted a multi-omics analysis. They discovered that lactate enhances histone acetylation, increasing chromatin accessibility of key genes, including the oncogene MYC. Concurrently, BRD4, which recognizes acetylated lysine residues, promotes MYC gene transcription, thereby elevating MYC protein levels. As a well-known transcription factor in the WNT pathway, MYC plays a critical role in regulating the stemness, proliferation, and migration of colorectal cancer cells. This clarifies the mechanism by which lactate maintains the population of CSCs in tumors. Finally, the researchers validated that both BRD4 inhibitors and MYC inhibitors can effectively suppress the increase in CSCs (Figure 1). The metabolic division of labor and dynamic interaction mechanism between CSC and CDC in intestinal tumors provide new insights into tumor heterogeneity and treatment resistance. This study revealed that CDC secretes lactate through high expression of MCT4, while CSC utilizes high mitochondrial activity and MCT1-mediated lactate uptake to form a “lactate cycle”, creating a metabolic symbiotic network. This metabolic coupling not only maintains the stemness of CSC but also promotes cell plasticity through lactate-mediated epigenetic reprogramming. Specifically, lactate activates BRD4 through epigenetic mechanisms (such as histone acetylation) and enhances MYC transcription. As a transcription factor, MYC can further regulate WNT-related genes, forming a positive feedback loop and amplifying WNT signals. The WNT/β-catenin pathway (especially overactivated by APC mutation in colorectal cancer) directly upregulates MYC transcription through the nuclear β-catenin/TCF/LEF complex to maintain stem cell characteristics and proliferation. These findings unveil a novel paradigm of metabolite-epigenetic coupling within the tumor ecosystem to regulate stem cell dynamics, suggesting that targeting the lactate-MYC axis could disrupt tumor cell plasticity and provide a breakthrough for overcoming treatment resistance. Although this study systematically elucidated the central role of lactate metabolism in tumor dynamics using organoid models and single-cell tracking technology, certain limitations should be acknowledged. The current model does not incorporate in vivo microenvironmental factors such as vascularization and immune interactions. For instance, tumor-associated macrophages (TAMs) secrete lactate under hypoxia, which could further amplify CSC plasticity via paracrine signaling. Conversely, lactate may suppress cytotoxic T-cell activity, creating an immune-evasive niche. Additionally, MYC inhibition only partially reverses the lactate effect, suggesting the involvement of other epigenetic regulatory mechanisms, such as lactylation modification [5]. Future studies should validate the regulatory role of lactate in metastasis and drug resistance using animal models and clinical samples. Integrating metabolic flux analysis with protein posttranslational modification omics will be essential to systematically decipher the metabolic-epigenetic interaction network. From a translational medicine perspective, developing novel inhibitors targeting lactate transporters (MCT1/4) or histone acetyltransferases (e.g., p300/CBP) and exploring their synergistic effects with existing BRD4 inhibitors could provide an effective strategy to overcome tumor metabolic adaptability. Furthermore, the development of diagnostic markers based on lactate levels and CSC abundance, combined with metabolic imaging technologies, will offer critical insights for personalized treatment strategies. Advancing these multi-dimensional research directions holds promise for achieving a breakthrough in clinical translation, shifting from “metabolic reprogramming” to “therapeutic reprogramming”. Yan Xue: writing – original draft, writing – review and editing. Lin-Zhu Zhang: conceptualization, funding acquisition, writing – review and editing. Both authors have read and approved the final manuscript. The study was funded by Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX25_0523) and SEU Innovation Capability Enhancement Plan for Doctoral Students (CXJH_SEU 25229). Figure was created by BioRender.com. The authors have nothing to report. The authors declare no conflicts of interest. The authors have nothing to report.