Lactate and lactylation play multifaceted roles in pancreatic ductal adenocarcinoma

The review details how lactylation, catalyzed by enzymes such as p300/CBP, alters protein function to promote tumor proliferation, perineural invasion, and an immunosuppressive microenvironment-for instance, by polarizing macrophages toward the M2 phenotype and inducing 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 work also evaluates therapeutic strategies targeting lactate metabolism, including inhibitors of lactate dehydrogenase A (LDHA) and monocarboxylate transporters (MCTs), and highlights their potential in combination with chemotherapy and immunotherapy.

Despite promising preclinical results, the authors caution that clinical translation faces significant hurdles, including systemic toxicity, metabolic plasticity, and the formidable desmoplastic barrier unique to PDAC. They advocate for future research integrating spatial transcriptomics and conditional knockout models to deconstruct tumor heterogeneity and develop site-specific inhibitors. This review provides a foundational framework for understanding lactate's regulatory network and offers new avenues for precision targeted therapies in one of the deadliest malignancies.

Source:

FAR Publishing Limited

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