The PDK/PDC-Lactate Axis: A Central Hub Intersecting Cancer Metabolism and Immunosuppression.

Abstract

Aberrant glucose metabolism is a hallmark of cancer metabolic reprogramming. The mitochondrial pyruvate dehydrogenase complex (PDC) acts as a central metabolic node that converts pyruvate into acetyl-CoA to sustain oxidative phosphorylation (OXPHOS). In tumor cells, however, overexpressed pyruvate dehydrogenase kinases (PDKs) phosphorylate and inactivate PDC, diverting carbon flux toward glycolysis and driving excessive lactate accumulation. Cumulative evidence demonstrates that microenvironmental lactate not only fuels tumor growth but also reshapes the tumor microenvironment (TME) into an immunosuppressive state that facilitates immune evasion. Conversely, pharmacological PDK inhibition effectively reverses this metabolic shift, depletes intratumoral lactate, restores mitochondrial pyruvate oxidation, and triggers tumor-selective apoptosis. Given these oncogenic and immunosuppressive functions, the PDC/PDK-lactate axis has emerged as a promising therapeutic target, prompting intensive research into the development of small-molecule PDK inhibitors. Here, we critically evaluate the evidence establishing this axis as a key driver of immune evasion. Unlike previous reviews that focused separately on metabolic or immunological aspects, this review uniquely integrates three emerging layers: (i) the isoform-selective functions of PDK1-4 in tumor metabolism and immune modulation; (ii) recently identified histone and non-histone lactylation as a direct epigenetic bridge connecting PDK activity to immune suppression; and (iii) a critical reappraisal of PDK inhibitors, with particular emphasis on the distinction between preclinical efficacy and clinical translation. Finally, we propose that isoform-selective targeting of PDK1 and PDK3, rather than pan-PDK inhibition, combined with immune checkpoint blockade, represents a promising strategy to overcome current therapeutic bottlenecks.

Abstract as supplied by the indexing source. © the authors / publisher.