The Emerging Challenge of Non-Cirrhotic MASLD-Related Hepatocellular Carcinoma: Etiology, Immunopathology, and Precision Oncology

Background: Hepatocellular carcinoma (HCC) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly identified in non-cirrhosis livers, representing a distinct clinical challenge. Unlike other etiologies, up to 50% of MASLD-related HCC arises without cirrhosis, conferring a significantly elevated risk and bypassing the traditional cirrhosis-carcinoma sequence. Summary: This review delineates the unique pathogenesis of non-cirrhotic MASLD-HCC, focusing on the interplay between metabolic dysregulation, chronic inflammation, and a characteristic immunosuppressive tumor microenvironment (TME). We synthesize evidence on how immune dysregulation – particularly involving dysfunctional CD8+ T cells and an altered myeloid compartment – facilitates hepatocarcinogenesis independent of advanced fibrosis. The roles of genetic susceptibility (e.g., PNPLA3 and TM6SF2 variants), gut-liver axis disruption, and distinct molecular traits are also examined. We further evaluate emerging biomarkers for risk stratification and discuss the implications of the non-cirrhotic MASH immune contexture for responses to immunotherapy. Key Messages: Non-cirrhotic MASLD-HCC is a distinct oncogenic entity driven by metabolic-immune interplay. Its recognition necessitates a shift in clinical paradigm: (1) surveillance strategies must incorporate metabolic and genetic risk factors beyond cirrhosis; (2) the unique TME may predict immunotherapy efficacy, urging etiology-specific trial design; and (3) a precision oncology framework integrating molecular subtyping and biomarker profiling is essential for early detection and tailored management of this growing patient population.