The immune microenvironment of steatotic hepatocellular carcinoma: Current findings and future prospects

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is notorious for its resistance to systemic treatments. The field has made a great leap in the past decade, with the number of FDA-approved therapies for advanced HCC increasing from 1 to 9. Although tyrosine kinase inhibitors remain the most common first-line option as monotherapy treatment, the clinical success of immune checkpoint inhibitors, especially when used in combination with anti-VEGF/VEGFR in HCC will likely transform the treatment landscape. While immune checkpoint inhibitors represent an exciting therapeutic revenue for HCC, recent studies have revealed that nonviral HCC, which is primarily caused by metabolic dysfunction-associated steatotic hepatitis (MASH), has a distinct and less favorable response to the immune checkpoint inhibitors. MASH is the most rapidly increasing etiology for HCC. The immune microenvironment of MASH-HCC is greatly affected by the intertwined pathological processes of steatosis-induced iterative cycles between steatohepatitis and liver injury. Here, we present a timely summary of the immune microenvironment of MASH-HCC. We will delve into the use of cutting-edge technologies, such as single-cell RNA sequencing, spatial transcriptomics, and mass cytometry imaging, to deconvolute the complexity of the immune ecosystem in MASH-HCC. We will also discuss the novel therapeutic innovations for MASH-HCC in preclinical models, such as the metabolic inhibitor, epigenetic inhibitor, and immunomodulator. These inhibitors all have the ability to subvert the immune microenvironment of MASH-HCC, improving the efficiency of anti-PD-1. While awaiting new drugs to be tested in clinical trials, the knowledge gained from these investigations is crucial for the development of personalized and effective treatment strategies for MASH-HCC.