A recent review published in Current Molecular Pharmacology examines the complex roles of lactate and its downstream protein modification, lactylation, in pancreatic ductal adenocarcinoma. The authors outline how metabolic reprogramming, influenced by oncogenic KRAS and a complicated tumor microenvironment, leads to significant accumulation of lactate. Rather than being only a glycolysis byproduct, lactate serves as an alternative metabolic fuel, acts as a signaling molecule activating pro-tumor pathways, and functions as a substrate for epigenetic regulation through histone and non-histone lactylation.
The review describes how enzymes such as p300/CBP catalyze lactylation, altering protein function to promote tumor proliferation, perineural invasion, and the creation of an immunosuppressive environment. For example, this process can polarize macrophages toward the M2 phenotype and induce T cell exhaustion. "Our analysis underscores that lactylation is not merely an intracellular feedback mechanism but a spatial signaling mediator that orchestrates multicellular communication within the dense stroma of PDAC," said the corresponding author, Dr. Zhe Liu.
The authors also evaluate therapeutic strategies targeting various aspects of lactate metabolism. These include inhibitors of lactate dehydrogenase A (LDHA) and monocarboxylate transporters (MCTs), which may be used in combination with chemotherapy or immunotherapy.
Despite encouraging results from preclinical studies on these therapies, challenges remain for clinical application. The authors cite systemic toxicity risks, metabolic plasticity within tumors, and the unique desmoplastic barrier found in pancreatic ductal adenocarcinoma as obstacles to translation into patient care.
They recommend future research use spatial transcriptomics and conditional knockout models to better understand tumor heterogeneity and develop site-specific inhibitors. According to the review's findings published on Jun. 25 by Dr. Liu's team, these approaches could provide new directions for precision targeted therapies against one of the most lethal forms of cancer.
