Liver cancer has long been one of the most stubborn opponents in oncology, and one of the main reasons is that hepatocellular carcinoma, the most common form of primary liver cancer, does not simply grow in a vacuum. It constructs an environment around itself that actively disarms the immune system. Immunotherapy, which has transformed the treatment of many other cancers, delivers only limited benefit to most patients with this disease. A new study published in the Journal of Translational Medicine by researchers at The First Affiliated Hospital of Zhengzhou University now reveals an unexpectedly elaborate molecular circuit that connects the waste products of tumor metabolism to the silencing of immune cells, and in doing so it points to a fresh set of therapeutic targets hidden deep inside the tumor microenvironment.
The centerpiece of the new work is a chemical modification called lactylation, a relatively recent addition to the catalog of post-translational modifications that biologists use to describe how proteins are tuned after they are made. Lactylation attaches a lactate-derived group to lysine residues, the same amino acid building blocks that carry many other regulatory marks. What makes this modification special is its origin: lactate is the end product of the fermentation metabolism that cancer cells rely on heavily even when oxygen is plentiful, a phenomenon known as aerobic glycolysis or the Warburg effect. Tumors therefore bathe their surroundings in lactate, and lactylation provides a direct mechanism by which this metabolic byproduct can be converted into epigenetic and proteomic instructions that reshape cell behavior.
To map the full landscape of this modification in liver cancer, the team carried out global lactylome profiling, using liquid chromatography-tandem mass spectrometry to identify precisely which proteins in hepatocellular carcinoma tissue carry lactylation marks and at which lysine positions. This unbiased survey was complemented by RNA sequencing, lipidomics to quantify the repertoire of fats and sterols inside tumors, and single-cell RNA sequencing to place the molecular findings within the complex cellular ecosystem of the tumor. The researchers also generated customized site-specific antibodies, tools that recognize lactylation at a single defined amino acid position on a single protein, allowing them to detect and manipulate one specific mark among thousands.
Two distinct lactylation events emerged as the critical nodes of the pathway. The first occurs on histone H3, one of the spool-like proteins around which DNA is wound. When lysine 18 of histone H3 is lactylated, a mark known as H3K18la, it acts on chromatin the way an open sign acts on a shop door: it makes nearby genes accessible for transcription. In this case, the gene switched on by H3K18 lactylation encodes METTL3, methyltransferase-like 3, the catalytic engine of the cell’s N6-methyladenosine machinery. m6A is the most abundant internal chemical modification of messenger RNA in mammals, and METTL3 is the enzyme that installs it. By raising METTL3 production through histone lactylation, the tumor effectively turns up the dial on RNA methylation across the cell.
The second event is more unusual and more conceptually striking. METTL3 itself, a protein rather than a stretch of DNA, is lactylated at lysine 27. This non-histone lactylation of METTL3 enhances its enzymatic activity, so the very methyltransferase whose production was boosted by histone lactylation is simultaneously activated by lactylation of its own structure. The result is a feed-forward arrangement in which lactate amplifies the m6A-writing apparatus at two independent levels. Once supercharged, METTL3 deposits m6A marks onto the messenger RNA of a specific target: FDFT1, farnesyl-diphosphate farnesyltransferase 1, the enzyme that catalyzes the first committed step of the cholesterol biosynthesis pathway, converting farnesyl pyrophosphate into squalene.
m6A marks on RNA do not act alone. They are read by a family of recognition proteins that determine the fate of the tagged transcript. The study identified IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2, as the reader that recognizes the METTL3-installed marks on FDFT1 messenger RNA. Rather than destroying the transcript, IGF2BP2 stabilizes it and promotes its translation into protein. The net effect of the entire cascade is a surge in FDFT1 protein, a surge in de novo cholesterol synthesis, and, as the lipidomics data confirmed, enhanced cholesterol efflux from the tumor cells into the surrounding microenvironment. Cholesterol, in this scenario, is not merely a building block for membranes; it functions as a signaling metabolite that reprograms neighboring immune cells.
The destination of that cholesterol signal is the tumor-associated macrophage, one of the most influential cell types in the tumor microenvironment. Macrophages are plastic cells that adopt distinct functional states: M1-like macrophages tend to attack tumors and rally anti-tumor immunity, whereas M2-like macrophages suppress immune responses, promote tissue remodeling, and support tumor growth. Using spontaneous orthotopic hepatocellular carcinoma mouse models, in which tumors arise in the liver and grow in their natural anatomical location, together with humanized orthotopic models carrying human immune cells, the researchers demonstrated that the cholesterol-rich environment driven by the lactylation cascade pushes tumor-associated macrophages toward the immunosuppressive M2 phenotype. Flow cytometry confirmed the shift in macrophage polarization states within the tumors.
The clinical implications of this mechanism are considerable. An immunosuppressive macrophage population is one of the central reasons why checkpoint inhibitor therapies underperform in liver cancer: even when T cells are unleashed, they enter a microenvironment thick with M2-polarized macrophages and other suppressive elements. By tracing that suppression back to a defined molecular axis, the H3K18la/METTL3-K27la/FDFT1 pathway, the study converts a diffuse problem into a set of addressable targets. Inhibiting lactate production or lactylation enzymes, blocking METTL3 activity, disrupting the IGF2BP2-FDFT1 interaction, or intervening in cholesterol biosynthesis and efflux each represents a potential point of attack, and combining such interventions with existing immunotherapy could theoretically relieve the immunosuppression that currently blunts treatment responses.
Methodologically, the study is notable for the breadth of its toolkit and the rigor of its validation. The investigators moved from unbiased lactylome discovery to mechanistic confirmation using methylated RNA immunoprecipitation to verify m6A deposition on FDFT1 transcripts, RNA immunoprecipitation to confirm the IGF2BP2 interaction, and chromatin-level analyses to establish the H3K18la-driven transcriptional activation of METTL3. The animal work was conducted under institutional ethics approval and in accordance with ARRIVE guidelines 2.0, and the human tissue component, which collected hepatocellular carcinoma specimens and paired peritumoral tissue from surgical patients with written informed consent, was approved by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University. The authors declared no competing interests, and the work received support from the National Natural Science Foundation of China and the Key Scientific Research Projects of Universities in Henan Province.
Beyond its immediate relevance to liver cancer, the research adds an important conceptual layer to a rapidly growing field. Lactylation was first described as a histone mark linking cellular metabolism to gene expression, but evidence has been accumulating that non-histone proteins are also extensively lactylated. This study is among the first to show, in a single connected pathway, how histone lactylation and non-histone lactylation cooperate: one mark turns a gene on, the other activates the protein that gene encodes, and the combined output rewires lipid metabolism to corrupt the immune landscape of a tumor. It is a vivid demonstration that metabolites can act as messengers across entirely different layers of biological regulation, from chromatin to RNA to lipid chemistry to immune cell behavior. For patients with hepatocellular carcinoma, whose options remain limited despite decades of effort, the identification of this lactylation-cholesterol-macrophage axis offers a genuinely new direction, one that treats the tumor’s metabolic exhaust not as waste but as the fuel of a communication network that medicine may now learn to cut.
Subject of Research: Lactylation-regulated cholesterol metabolic reprogramming and macrophage polarization in hepatocellular carcinoma
Article Title: Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma
Article References: Zhai, Y., Zhao, H., Wang, Z., Zhang, Y., Zhao, S., Wang, C., Liu, Y., Cao, J., Lin, C., Wu, Y., Liang, R., Zhu, R., Wang, W., Li, J., & Sun, Y. (2026). Lactylation-regulated METTL3-mediated cholesterol metabolic reprogramming via FDFT1 facilitates macrophage polarization in hepatocellular carcinoma. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08870-z
Image Credits: AI Generated
DOI: 10.1186/s12967-026-08870-z
Keywords: hepatocellular carcinoma, lactylation, METTL3, m6A methylation, FDFT1, cholesterol metabolism, macrophage polarization, tumor microenvironment, IGF2BP2, H3K18la, immunosuppression, tumor-associated macrophages
News Source: Nathaniel Bowman. (October 9, 2026). Lactate Fuels a Hidden Molecular Chain That Helps Liver Cancer Evade Immunity. Scienmag.
