Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments

Vollständiger Abstract

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Abstract Lactate and lactate-mediated protein lactylation are no longer viewed merely as accompanying phenomena of enhanced glycolysis, hypoxic responses, or tissue acidification. They are now recognized as an important regulatory axis that links local metabolic stress to chromatin regulation and altered protein function. With the rapid development of research on histone and non-histone lactylation, lactate-related signals have been implicated in inflammatory injury and repair, fibrotic remodeling, tumor immune escape, and therapy resistance. However, current studies often conflate elevated lactate levels, global increases in lactylation, site-specific lactylation events, and disease-dependent functional consequences, which can lead to overinterpretation of both the biological impact and therapeutic value of lactylation. This review first summarizes lactate production, transport, and local homeostatic regulation, then discusses the biochemical basis and detection strategies of protein lactylation. It further examines how histone lactylation reshapes transcriptional programs and how non-histone lactylation influences immune regulation by altering protein fate and signaling execution. Considering the distinct features of inflammatory and tumor microenvironments, this review compares the functional outputs of the lactate–lactylation axis during stage-specific inflammatory responses and persistent tumor-associated stress, with particular emphasis on its translational significance in immune checkpoint regulation, impaired antigen presentation, and therapeutic resistance. We propose a stratified framework for interpreting lactate-related events, distinguishing metabolic stress readouts, functional regulatory events, and disease-dependent nodes. This framework may support patient stratification, lesion-selective delivery, dynamic monitoring, and the design of precise combination therapies.