From MASLD to HCC: What's in the middle?

Abstract

Metabolic dysfunction associated steatotic liver disease (MASLD) is a progressive pathological condition characterized by the accumulation of triglycerides within hepatocytes that causes histological changes, which, in the long run, might compromise liver functional capacities. MASLD predisposes to metabolic dysfunction-associated steatohepatitis (MASH), in which the persistence of inflammatory reactions perpetuates tissue injury and induces alterations of the extracellular matrix, leading to liver fibrosis and cirrhosis. Furthermore, these processes are also fertile ground for the development of hepatocellular carcinoma (HCC). In this latter respect, growing evidence suggests that chronic inflammation not only acts as the primary stimulus for hepatocellular malignant transformation, cell proliferation and cancer cell progression but also reshapes the immune landscape, inducing immune system exhaustion and favoring the loss of cancer immune surveillance. Therefore, a thorough understanding of the cellular and molecular mechanisms orchestrating hepatic inflammatory responses may open the way for fine-tuning therapeutic interventions that could, from one side, counteract MASLD progression and, on the other one, effectively treat HCCs.

Keywords: Chronic inflammation; HCC; Immunity; Immunotherapies; MASH; MASLD.

Fig. 1

Overview of the cellular and molecular mechanisms that underlie the transition from MASLD to MASH-related HCC. MASLD-associated metabolic dysfunctions cause oxidative stress, cell death and chronic inflammation. The persistence of inflammatory responses reshapes the hepatic immune landscape with the loss of effector T cells accompanied by an expansion of exhausted T cells, dysfunctional NK/NKT cells and multiple immunosuppressive cell subsets. In parallel, the cytokine milieu undergoes profound modifications because of the predominant production of immunomodulatory molecules. These overall changes lead to a cancer-prone immune microenvironment where transformed malignant hepatocytes can grow undisturbed. FFA, free fatty acid; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; OPN, osteopontin; Gal-3, galectin-3; OSAs, oxidative stress derived antigens; MDSC, myeloid-derived suppressor cell; TAMs, tumor-associated macrophages. Image created with BioRender.com.