The PI3K/Akt/mTOR Pathway: Immuno-Metabolic Orchestration in IR/MASH-Associated Hepatocellular Carcinoma

Abstract

Insulin resistance (IR) and Metabolic Dysfunction-Associated Steatohepatitis (MASH) are key drivers of hepatocellular carcinoma (HCC), yet the mechanisms underlying their induction of an immunosuppressive tumor microenvironment (TME) require elucidation. This review posits that the PI3K/Akt/mTOR signaling pathway acts as the central integrator of this process, becoming fundamentally rewired—or “imprinted”—by the unique pathological context of IR/MASH-HCC. We highlight how this “imprinted” pathway integrates disparate pathological signals to precisely direct tumor metabolic reprogramming, TME immune landscape remodeling, and the metabolic-dependent regulation of immune cells. We particularly dissect the synergistic amplification of pathway-mediated immune evasion (including PD-L1 upregulation and EMT) by the IR/MASH microenvironment. This integrated framework, which conceptualizes the pathway as the central processing unit of a uniquely aggressive immuno-metabolic phenotype, not only illuminates the unique biology of IR/MASH-HCC but also provides new insights and a theoretical basis for the clinical translation of targeting the PI3K/Akt/mTOR pathway—encompassing novel combination strategies and biomarker development—to foster more effective clinical interventions.