Lactate modification fuels drug resistance and immune escape in cancer

Published in Current Molecular Pharmacology, a comprehensive review led by Yong Xu and colleagues from Shanghai Pulmonary Hospital explores the emerging role of lactylation, a post-translational modification driven by lactate, in lung cancer progression and drug resistance. The authors explain that lactate, once considered a metabolic waste product, now stands at the center of a signaling hub that connects metabolism to epigenetics.

Lactylation functions as a hidden metabolic key player that reprograms the epigenetic state of tumor cells and fuels multiple drug resistance mechanisms."

Yong Xu, corresponding author

The review systematically describes the "reflex arc" of lactylation regulation: writers (such as p300 and AARS1/2) sense lactate and install lactyl marks, erasers (HDACs and SIRT1/3) remove them, and readers like BRG1 execute downstream transcriptional programs. In lung cancer, histone H3K18 lactylation promotes immune escape via the POM121/MYC/PD-L1 axis in non-small cell lung cancer and the LDH-H3K18la-Nur77 axis in small cell lung cancer. The review also highlights self-reinforcing loops-such as the CTHRC1/glycolysis/H3K18la and NNMT-EGR1-lactate axes-that sustain acquired resistance to EGFR-TKIs.

The authors conclude that targeting lactylation writers, reducing lactate production, or disrupting these feedback loops may reverse resistance and restore treatment efficacy.

"This framework provides a new perspective for overcoming tumor treatment resistance and developing precision therapies," Xu added.