Lactylation: a novel driver of drug resistance in the tumor microenvironment

Lactylation, a novel lactate-derived lysine post-translational modification (PTM), has emerged as a critical epigenetic regulator driving drug resistance within the tumor microenvironment (TME). This review systematically delineates the enzymatic underpinnings of lactylation, its induction via the glycolysis-lactate axis influenced by key TME features (hypoxia, inflammation), and its multifaceted roles in promoting resistance. Specifically, lactylation orchestrates transcriptional reprogramming of resistance-associated genes (e.g., oncogenes, immune checkpoints, epithelial–mesenchymal transition factors), enhances DNA damage repair capacity (e.g., via NBS1/MRE11 lactylation), activates pro-survival autophagy, and modulates immunosuppressive signaling pathways (e.g., PI3K/AKT, NF-κB, JAK/STAT). Furthermore, it facilitates critical resistance phenotypes including immune evasion, metastasis, and angiogenesis. The review summarizes emerging therapeutic strategies targeting lactylation, such as inhibition of lactate production (LDHA/LDHB), lactate transport (MCT1/4), lactyltransferases (e.g., p300), or downstream effectors, highlighting their potential to overcome multifactorial resistance. However, elucidating the context-dependent roles, crosstalk with other PTMs, and developing specific inhibitors remain crucial for translating these insights into effective clinical interventions against resistant tumors.