For decades, lactate was considered little more than an inconvenient byproduct of cellular metabolism—famous for building up in muscles during intense exercise and causing fatigue. In oncology, it was even viewed as a passive result of the accelerated metabolism of tumor cells. However, recent years have brought a radical shift: new research shows that lactate not only actively participates in cancer biology but can also shape treatment responses and, paradoxically, become a therapeutic ally.
At the heart of this paradigm shift is lactylation, a type of post-translational chemical modification in which lactate molecules attach to lysine residues in key proteins. This small “coupling” alters protein structure and function, which can influence everything from how cells use energy to the expression of genes involved in cell proliferation, DNA repair, or immune response.
The Warburg Effect and Lactate Accumulation
The starting point for this story lies in a metabolic feature known as the Warburg effect, described by Otto Warburg in the 20th century. Unlike normal cells, which primarily use mitochondrial respiration to generate energy, cancer cells rely heavily on glycolysis even when oxygen is available. This not only allows them to produce energy quickly but also to generate a large amount of metabolites that favor their growth, including lactate.
Far from being inert, this lactate is actively exported out of tumor cells through specialized transporters (MCTs), flooding the tumor microenvironment with excess lactic acid. This acidic, lactate-rich environment is no accident—it weakens the function of immune cells that could attack the tumor, promotes the formation of new blood vessels to feed it (angiogenesis), and stimulates genetic and epigenetic changes that reinforce cancer survival.
Lactylation: A New Player in Tumor Biology
Lactylation occurs when lactate covalently attaches to proteins, either via enzymatic mechanisms—using lactyl-CoA as an intermediate—or non-enzymatic pathways—through compounds like lactyl-glutathione. This modification affects both non-histone proteins (involved in metabolism, signaling, and repair) and histones, the proteins around which DNA is wrapped.
In the nucleus, histone lactylation can change how chromatin is packaged, activating or silencing specific genes. For example, lactylation of histone H3 at lysine 18 (H3K18la) has been linked to the activation of genes that allow tumor cells to evade the immune response or repair DNA damage—processes that translate into resistance to therapies such as radiotherapy or certain drugs.
Impact on Immunotherapy: Lactate’s Double-Edged Sword
In immunotherapy, the goal is to stimulate the body’s natural defenses to recognize and destroy cancer cells. However, lactate accumulation and associated lactylation can undermine this effort in several ways:
Direct immunosuppression: Lactate can slow down the mobility and killing capacity of CD8+ T cells and NK cells, which are responsible for eliminating tumor cells.
Promoting regulatory cells: It enhances the expansion of regulatory T cells (Tregs) and M2-type macrophages, both of which specialize in suppressing inflammatory responses and protecting the tumor.
Interference with immune checkpoints: Studies show that lactate uptake by Tregs can increase PD-1 expression, a protein that inhibits T cell activity. This can reduce the effectiveness of drugs that block PD-1/PD-L1—one of the cornerstones of modern immunotherapy.
Yet here lies the paradox: if we learn to manipulate lactylation, we might achieve the opposite effect—making immune cells function better and respond more strongly to therapies.
In Radiotherapy: Between Resistance and Opportunity
Radiotherapy damages the DNA of tumor cells, but many manage to repair it and survive. Lactylation intervenes in this process by modifying key DNA repair proteins, such as NBS1, increasing their efficiency and thus the tumor’s resistance.
On the other hand, modulating lactylation could weaken these repair mechanisms and sensitize tumors to radiation, improving outcomes. This is especially promising in highly resistant cancers like glioblastoma or pancreatic cancer.
Moreover, radiotherapy does not act only locally—in some cases, it can trigger the abscopal effect, in which the destruction of a treated tumor causes regression of other tumors in the body through immune activation. Regulating lactylation could enhance this phenomenon, achieving a more pronounced systemic benefit.
Fig. 1. The Warburg effect in cancer cells leads to excess extracellular lactate, creating an acidic tumor microenvironment. This promotes immune suppression, pro-tumor gene activation via histone modifications, and increased genomic instability—effects that can be exploited to enhance therapy.
Lactylation as a Biomarker and Therapeutic Target
One of the most exciting advances is the potential of lactylation as a biomarker. Analyzing its levels and patterns could help predict whether a patient will respond well to immunotherapy, radiotherapy, or combinations of both.
In parallel, researchers are developing specific inhibitors for the enzymes that control lactylation, as well as strategies to modify lactate metabolism. This opens the door to personalized treatments that focus not only on killing tumor cells but also on disabling their metabolic and epigenetic defenses.
Technologies such as nanoparticles are also being explored to deliver these treatments precisely to the tumor microenvironment, reducing side effects and maximizing efficacy.
Looking to the Future
Lactylation is a relatively new field but one with enormous potential to change the way we understand and treat cancer. It acts as a bridge between metabolism and epigenetics, and its strategic manipulation could break the barriers that currently limit the effectiveness of powerful therapies such as immunotherapy or radiotherapy.
If current progress continues, it is possible that in the coming years we will see combined protocols where regulating lactylation is as important as administering a drug or applying radiation, marking the beginning of an era in which the tumor’s own metabolism becomes its Achilles’ heel.
Main reference:
Yu, D., Zhong, Q., Wang, Y., Yin, C., Bai, M., Zhu, J., Chen, J., Li, H., & Hong, W. (2025). Lactylation: The metabolic accomplice shaping cancer’s response to radiotherapy and immunotherapy. Ageing research reviews, 104, 102670. https://doi.org/10.1016/j.arr.2025.102670
Other references:
Apostolova, P., & Pearce, E. L. (2022). Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment. Trends in immunology, 43(12), 969–977. https://doi.org/10.1016/j.it.2022.10.005
Arina, A., Gutiontov, S. I., & Weichselbaum, R. R. (2020). Radiotherapy and Immunotherapy for Cancer: From “Systemic” to “Multisite”. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(12), 2777–2782. https://doi.org/10.1158/1078-0432.CCR-19-2034
Bourillon, L., Bourgier, C., Gaborit, N., Garambois, V., Llès, E., Zampieri, A., Ogier, C., Jarlier, M., Radosevic-Robin, N., Orsetti, B., Delpech, H., Theillet, C., Colombo, P. E., Azria, D., Pèlegrin, A., Larbouret, C., & Chardès, T. (2019). An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer. International journal of cancer, 145(7), 1838–1851. https://doi.org/10.1002/ijc.32273
