Targeting sterol O-acyltransferase 1 rewires fatty acid metabolism and uncovers immune vulnerability in hepatocellular carcinoma

Background and Aims: The development of hepatocellular carcinoma (HCC) is intricately linked to metabolic processes and immune evasion strategies. As an emerging metabolic vulnerability in HCC, the detailed molecular mechanisms of sterol O-acyltransferase 1 (SOAT1) and its role in immune regulation remain unclear. This study aimed to elucidate the mechanism involved and evaluate the potential of SOAT1 as a therapeutic target. Approach and Results: We explored the role of SOAT1 using genetical and pharmaceutical inhibition in cell lines, patient-derived organoids, and mouse models. Co-culture systems, flow cytometry, and immunohistochemistry were employed to assess tumor–immune interactions. Multi-omics were performed to elucidate the underlying molecular mechanisms. The efficacy of inhibiting SOAT1 alone and in combination with anti-PD1 therapy in vivo was tested. SOAT1 was significantly upregulated in HCC tumors and was associated with increased tumorigenicity and immune-evasive characteristics. SOAT1 deficiency disrupted lipid homeostasis, leading to the accumulation of saturated fatty acids, reactive oxygen species, and endoplasmic reticulum stress, followed by NF-κB activation. This signaling triggered the production of pro-inflammatory cytokines, adhesion molecules, and the recruitment of CD11c + antigen-presenting cells and cytotoxic CD8 + T cells into tumors. Moreover, SOAT1 knockout reduced tumor burden, and the combination of SOAT1 inhibition with PD-1 blockade exhibited synergistic antitumor effects. Conclusions: SOAT1 functions as both a metabolic vulnerability and an immune regulator in HCC. Its inhibition disrupts tumor-promoting metabolic processes while enhancing immune activation, presenting it as a promising therapeutic target. Combining SOAT1 inhibition with PD-1 blockade holds potential for improving outcomes in HCC immunotherapy.