Metabolic memory and immune evasion in MASLD-HCC progression

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of hepatocellular carcinoma (HCC). Central to its pathogenesis is “metabolic memory” - the persistence of pro-tumorigenic alterations after resolution of the initial metabolic insult. This review examines how metabolic memory, encoded across multiple layers of the epigenome - including DNA methylation, repressive histone modifications, and non-coding RNA networks - and propagated through mitochondrial dysfunction and lipotoxic metabolites, sustains a locked immunosuppressive state that drives immune evasion in MASLD-HCC. We delineate convergent pathways - including the unfolded protein response, dysregulated autophagy, tryptophan-kynurenine-aryl hydrocarbon receptor (AHR) signaling - that couple metabolic memory to immune checkpoint upregulation and T-cell exhaustion. We further discuss how metabolic byproducts such as lactate drive immunosuppression through histone lactylation, and how extracellular vesicles transmit metabolic stress signatures to remotely reprogram immune cells within the tumor microenvironment. From a therapeutic perspective, we evaluate strategies targeting the reversibility of this memory, including NAD+-SIRT3 axis restoration and epigenetic modulators such as HDAC inhibitors, and discuss their potential to sensitize tumors to immunotherapy. We also explore emerging approaches aimed at disrupting the kynurenine-AHR axis and overcoming fibrotic barriers to immune infiltration. Disrupting this “epigenetic-metabolic-immune axis” may be essential for halting disease progression.