Lactylation: The Hidden Driver of Lung Cancer Resistance

A growing body of evidence positions lactylation, a lactate-induced protein modification, as a hidden driver of lung cancer (LC) malignancy and treatment failure. According to a comprehensive review published in Current Molecular Pharmacology, abnormal lactylation of histones and non-histone proteins fuels tumor proliferation, immune suppression, and resistance to standard therapies.

The review, led by Yong Xu at Shanghai Pulmonary Hospital, Tongji University, synthesizes findings from 2019 to 2025. The authors propose a “reflex arc” model: metabolic sensors (writers such as p300/CBP and AARS1) add lactyl marks, erasers (HDAC1–3 and SIRT1/3) remove them, and readers (e.g., BRG1) execute transcriptional programs. "Lactylation acts as a metabolic switch that reprograms gene expression and locks tumor cells into a resistant state," Xu explains.

In non-small cell lung cancer, H3K18 lactylation drives PD-L1 expression via the POM121/MYC axis, promoting immune escape. In small cell lung cancer, the LDH-H3K18la-Nur77 pathway impairs CD8+ T-cell function. The modification also sustains EGFR-TKI resistance through positive feedback loops, including CTHRC1/glycolysis/H3K18la and NNMT-EGR1-lactate.

The authors highlight that targeting lactate production or lactylation enzymes—such as LDHA, HBO1, or the RBM15-METTL3 m6A axis—could reverse resistance. "Understanding this network opens new avenues for combination therapies, including metabolic inhibitors plus checkpoint blockade," says Xu. The team calls for biomarker-driven trials using H3K18la immunohistochemistry or lactate imaging to select patients who may benefit from disrupting the lactylation cascade.