Immunotherapy resistance in MASLD-related hepatocellular carcinoma: special immune microenvironment and gut...

Obesity represents a major global public health challenge. Consequently, metabolic dysfunction-associated steatotic liver disease (MASLD) has become the primary driver of chronic liver disease globally and is currently the most rapidly accelerating factor contributing to hepatocellular carcinoma (HCC). However, current evidence indicates that immunotherapy, a cornerstone of HCC management, yields suboptimal results specifically in MASLD-related HCC (MASLD-HCC) cases. Various immune components constitute a special immune microenvironment in MASLD-HCC, including heterogeneous myeloid cells, lymphocytes and platelets. Furthermore, disruptions in the intestinal barrier, along with the ectopic presence of intestinal flora and metabolites, also influence the immune microenvironment in MASLD-HCC. Elucidating immune cells functions and their interplay with gut microbiota is critical to deciphering MASLD progression to carcinogenesis and immunotherapy resistance. This review synthesizes current insights into the immune microenvironment and gut microbiome in MASLD-HCC, identifies factors influencing the efficacy of immunotherapy, and summarizes potential therapeutic targets to provide detailed guidance for developing effective immunotherapy strategies for MASLD-HCC.