Research progress on lactate metabolism in lung cancer: Tumorigenesis, drug resistance and clinical translation (Review)

Therapeutic resistance is the main obstacle to long‑term survival in lung cancer, with metabolic reprogramming identified as a key factor in this failure. Accumulating evidence suggests that metabolic reprogramming, particularly the aberrant metabolism of lactate, plays a crucial role in the progression of lung cancer and the failure of treatment. Beyond its traditional characterization as a metabolic byproduct, lactate is increasingly recognized as a multifunctional signaling metabolite that connects tumor‑intrinsic metabolic adaptation with the remodeling of the tumor microenvironment. In the context of lung cancer, an increase in aerobic glycolysis and dysregulated lactate transport result in the persistent accumulation of lactate and extracellular acidification. This metabolic environment fosters tumor invasion, epithelial‑mesenchymal transition and the acquisition of cancer stemness, in part through lactylation‑mediated epigenetic reprogramming. Importantly, emerging research indicates that lactate metabolism serves as a unifying mechanism underlying resistance to chemotherapy, targeted therapy, immunotherapy and radiotherapy in lung cancer. Lactate‑driven metabolic support, signaling pathways and epigenetic modifications collectively establish a self‑reinforcing network of resistance across multiple treatment modalities. Key metabolic enzymes and transporters, such as lactate dehydrogenase and monocarboxylate transporters, function as critical regulatory nodes in this process. The present review aimed to summarize recent advancements in lactate production, transport and signaling in lung cancer, with a particular focus on the remodeling of the tumor microenvironment and pan‑therapeutic resistance. The present review discusses novel lactate‑related biomarkers and treatment approaches, focusing on their existing translational limitations.