Immunometabolic reprogramming of the HCC tumor microenvironment via nutritional metabolites: how bile acids, SCFAs, and sphingolipids reshape macrophage polarization, T-cell exhaustion, and the response to anti-PD-1 therapy

Hepatocellular carcinoma (HCC) represents one of the most lethal malignancies worldwide, with limited therapeutic efficacy despite advances in immune checkpoint inhibitor (ICI) therapy. The tumor microenvironment (TME) in HCC is characterized by profound metabolic alterations that critically influence immune cell function. This review examines the immunometabolic reprogramming of the HCC microenvironment mediated by three key classes of nutritional metabolites: bile acids, short-chain fatty acids (SCFAs), and sphingolipids. Studies have provided mechanistic insights into metabolite-driven immune cell reprogramming. Bile acids, particularly through the activation of FXR and TGR5 receptors, orchestrate macrophage polarization dynamics, with secondary bile acids such as deoxycholic acid (DCA) promoting M2-like tumor-associated macrophage (TAM) polarization conducive to tumor progression. SCFAs, including butyrate and propionate, enhance CD8+ T-cell functionality and improve anti-PD-1 therapeutic responses by modulating T-cell receptor signaling and memory formation. Sphingolipids, especially ceramides and sphingosine-1-phosphate, regulate T-cell exhaustion programs and natural killer T (NKT) cell activation, with distinct sphingolipid species exhibiting opposing effects on antitumor immunity. Nutritional metabolites function as critical signaling molecules that reshape the immunosuppressive HCC microenvironment. Understanding these immunometabolic crosstalk pathways offers novel therapeutic avenues for overcoming resistance to anti-PD-1 therapy and improving patient outcomes.