Lactate Tag on Histones Fuels Drug Resistance in Head and Neck Cancer

Scientists studying head and neck squamous cell carcinoma, one of the most common and difficult-to-treat cancers worldwide, have uncovered a molecular mechanism that explains why many patients stop responding to a widely used class of targeted drugs. The new research, published in the Journal of Translational Medicine, reveals that a chemical modification known as histone lactylation acts as a master switch that drives tumor growth and undermines EGFR-targeted therapy. The finding points to a promising therapeutic vulnerability that could be exploited with existing experimental compounds, and it adds fresh momentum to the growing field of research linking cellular metabolism directly to gene control in cancer.

The story begins with lactate, a molecule long dismissed as little more than a metabolic waste product. Cancer cells famously consume enormous amounts of glucose and ferment it into lactate even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the Warburg effect. In 2019, researchers discovered that lactate is not merely discarded; it can be chemically attached to lysine amino acids on proteins, including the histones around which DNA is wound. This modification, called lactylation, can loosen chromatin and activate gene expression, effectively allowing a metabolic byproduct to rewrite the instructions a cell follows. Since that discovery, scientists have raced to determine which lactylation marks matter most in which cancers, and whether blocking them could stall tumor progression.

In the new study, a research team led by Chuang Fu and Zhi-Zhou Shi of Kunming University of Science and Technology focused on a specific mark: lactylation at lysine 18 of histone H3, abbreviated H3K18la, in head and neck squamous cell carcinoma, or HNSCC. The team first showed that hypoxia, the oxygen-starved conditions typical of solid tumors, increased both H3K18la levels and the abundance of EGFR, the epidermal growth factor receptor that is a major therapeutic target in this disease. Single-cell RNA sequencing analysis of patient-derived data revealed a high-lactylation state within HNSCC cells, confirming that the modification is a prominent feature of the tumor landscape rather than a laboratory artifact.

To test whether this mark actually drives malignant behavior, the researchers manipulated lactylation pharmacologically. When they treated HNSCC cells with 2-deoxyglucose, a compound that blocks glycolysis, or with oxamate, an inhibitor of lactate dehydrogenase that prevents lactate production, the cells proliferated more slowly and formed fewer colonies. Critically, adding lactate back into the culture medium reversed these effects, restoring the cells’ growth advantage. This gain-and-loss evidence established that lactate availability, funneled into histone lactylation, directly supports the proliferative engine of the cancer cells, rather than being an incidental byproduct of their altered metabolism.

The next challenge was identifying which genes the mark actually controls. The team combined RNA sequencing, which measures gene expression, with CUT&Tag, a technique that maps where specific histone modifications sit along the genome. The integrated analysis revealed that H3K18 lactylation was strongly enriched at the locus encoding GLI2, a transcription factor best known as a downstream effector of the Hedgehog signaling pathway. The lactylation mark at the GLI2 locus was associated with transcriptional activation, meaning the epigenetic tag was literally switching on a potent pro-growth gene. Functional experiments confirmed the point: knocking down or inhibiting GLI2 suppressed HNSCC cell proliferation and colony formation, while overexpressing GLI2 promoted those same malignant phenotypes.

Having identified the mark and one of its key targets, the researchers asked which enzyme writes it. Attention turned to CBP, a well-known histone acetyltransferase that had previously been implicated as a lactyltransferase in other contexts. Molecular docking simulations predicted a binding interaction between CBP and the lactylated H3K18 mark, and co-immunoprecipitation experiments confirmed that the two proteins physically associate. When the team knocked down CBP, or treated cells with the CBP inhibitor SGC-CBP30 or the compound C646, H3K18la levels fell, GLI2 expression dropped, and HNSCC cells lost much of their capacity to proliferate and form colonies. In short, CBP emerged as the writer of the lactylation mark that sustains the GLI2 program.

The most clinically consequential part of the study concerns EGFR-targeted therapy. Drugs such as gefitinib and cetuximab, which block EGFR signaling, are standard options for subsets of HNSCC patients, but resistance frequently develops and limits their long-term benefit. The researchers found that EGFR itself sits upstream of the lactylation machinery: knocking down EGFR, or treating cells with gefitinib or cetuximab, reduced global protein lactylation, lowered H3K18la, and suppressed GLI2 expression. EGFR inhibition also decreased intracellular lactate concentrations and reduced glucose uptake, suggesting that EGFR signaling feeds the glycolytic flux that generates the lactate substrate for histone modification. Mechanistically, the team showed that EGFR binds to and stabilizes GLUT3, a glucose transporter, thereby helping the cancer cells maintain their sugar supply and, by extension, their lactylation program.

This wiring suggested a strategy: if the lactylation-GLI2 axis helps tumors survive EGFR blockade, then disabling that axis should resensitize them to the drugs. That is precisely what the experiments showed. Inhibitors acting on the H3K18la-GLI2 axis made HNSCC cells more vulnerable to both gefitinib and cetuximab in culture. More strikingly, in mouse xenograft models derived from CAL27 HNSCC cells, combining the CBP inhibitor SGC-CBP30 with gefitinib greatly improved the anti-tumor effects of the EGFR drug compared with either agent alone. The team also established gefitinib-resistant HNSCC cell lines and found that the H3K18la-GLI2 axis was activated in the resistant cells, and that blocking the pathway overcame that resistance. Together, these results position histone lactylation not just as a marker of aggressive disease but as an actionable driver of therapeutic failure.

The implications extend beyond head and neck cancer. Histone lactylation has now been implicated in multiple tumor types and in inflammatory and fibrotic diseases, and the identification of a defined writer-enzyme, mark, and target-gene cascade gives researchers a concrete axis to interrogate in other settings where EGFR inhibitors are used, including lung cancer. The study also highlights the value of pairing metabolic interventions with epigenetic drugs: because the lactylation mark depends on glycolysis-derived lactate, combinations that attack both the metabolic supply line and the epigenetic reader-writer machinery may prove more effective than either approach alone. Compounds such as 2-deoxyglucose and SGC-CBP30 are experimental tools rather than approved therapies, so translating these findings into the clinic will require careful dose-finding, safety evaluation, and biomarker development.

For patients with HNSCC, whose treatment options narrow sharply once EGFR-targeted agents stop working, the research offers a mechanistic explanation for resistance and a rational combination strategy to test in future trials. The work, funded by programs in Yunnan Province, China, and conducted under approved animal ethics protocols, exemplifies a broader shift in cancer biology: the recognition that the chemical state of chromatin is not fixed but is continuously shaped by the metabolic environment of the tumor. As lactylation research matures, the dream of turning a cancer cell’s own waste product against it, by blocking the enzymes that convert that waste into a growth-promoting epigenetic signal, moves one step closer to reality.

Subject of Research: Histone H3K18 lactylation in head and neck squamous cell carcinoma progression and EGFR-targeted therapy resistance

Article Title: CBP-mediated H3K18 lactylation drives GLI2 transcription to promote progression and EGFR-targeted therapy resistance in head and neck squamous cell carcinoma

Article References: Fu, C., Zhang, X.-G., Li, W.-T., Jiang, W., Fan, S.-C., & Shi, Z.-Z. (2026). CBP-mediated H3K18 lactylation drives GLI2 transcription to promote progression and EGFR-targeted therapy resistance in head and neck squamous cell carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09049-2

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09049-2

Keywords: histone lactylation, H3K18la, head and neck squamous cell carcinoma, EGFR, GLI2, CBP, gefitinib resistance, lactate, GLUT3, epigenetics, targeted therapy, cancer metabolism