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, 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 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 anti-tumor effects. CONCLUSION 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.