Liver cancer treatment has always been a clinical challenge. Traditional treatments often yield limited effectiveness due to rapid tumor progression and high molecular heterogeneity. Finding targets that simultaneously address tumor metabolism and immune evasion has become crucial for overcoming treatment bottlenecks. Recently, Hepatology published a new study by a team from the University of Hong Kong titled "Targeting sterol O-acyltransferase 1 rewires fatty acid metabolism and uncovers immune vulnerability in hepatocellular carcinoma." They focused on sterol O-acyltransferase 1 (SOAT1), discovering that this protein is not only a metabolic vulnerability point in liver cancer but also regulates the tumor immune microenvironment, bringing a new "two-pronged" strategy to liver cancer treatment.
The team first identified SOAT1 through a three-layer screening process. They screened metabolic targets affecting cell survival from hepatocellular carcinoma (HCC) cell lines, validated the therapeutic effect in patient-derived organoids, and assessed the impact on immunity using mononuclear cell migration assays, ultimately confirming SOAT1 as the core target. SOAT1 expression in HCC tissue was significantly higher than in normal liver tissue, while SOAT2 showed no significant change. Higher SOAT1 expression was associated with a greater likelihood of venous invasion, advanced tumor progression, and shorter overall survival. Approximately 20% of HCC patients exhibited altered SOAT1 gene copy number, which was directly correlated with increased mRNA expression, strongly suggesting that SOAT1 is a key oncogenic factor in HCC.
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To validate SOAT1 function, the team conducted a series of experiments. Knocking down SOAT1 or treating with the SOAT1 inhibitor avaximately bismuth significantly slowed the proliferation rate of HCC cells and significantly inhibited the growth of patient-derived organoids. The effects were even more pronounced in mouse models. After SOAT1 knockdown, the volume of orthotopic xenografts decreased, and lung metastases were reduced. Reintroducing wild-type SOAT1 into cells restored tumor proliferation. However, introducing the catalytically inactivated SOAT1 mutant had no effect, indicating that SOAT1's pro-cancer effect depends on its normal catalytic activity and is highly specific.
Mechanistically, the changes brought about by SOAT1 inhibition go far beyond cholesterol metabolism. It leads to the accumulation of long-chain fatty acids (especially C16:0, C18:0, and C18:1) intracellularly, causing lipid toxicity. Simultaneously, reactive oxygen species production increases, and the endoplasmic reticulum enters a state of stress. These metabolic disturbances further activate the NF-κB signaling pathway, promoting the production of pro-inflammatory cytokines such as CXCL16, CXCL12, and CX3CL1, as well as adhesion molecules such as ICAM-1. These molecules act as "navigation signals," guiding CD11c+ antigen-presenting cells and cytotoxic CD8+ T cells to infiltrate the tumor.
Figure 1. SOAT1 modulates tumor-immune crosstalk. (Ma H, et al. Hepatology)
After SOAT1 inhibition, immune cells no longer remain only at the tumor periphery but can diffusely infiltrate into the tumor interior. Flow cytometry and immunofluorescence results showed a significant increase in the number of CD11c+ cells within the tumor. These cells also co-localized with MHC class I and MHC class II molecules, enhancing antigen presentation capabilities. In vitro co-culture experiments also confirmed that SOAT1 inhibition promotes monocyte migration, increases CD11c expression, enhances the killing ability of CD8+ T cells, and reduces the proportion of PD1-positive exhausted CD8+ T cells.
In a mouse model of liver cancer, researchers combined avaxithib with an anti-PD-1 antibody and found that its tumor-suppressive effect far exceeded that of single therapy. Tumor volume shrank more significantly, and the tumor burden was significantly reduced. This is because SOAT1 inhibition first improves the tumor immune microenvironment, turning the previously "immune cold zone" into an "immune hot zone," and then, combined with a PD-1 inhibitor to relieve immunosuppression, the two work synergistically.
Figure 2. SOAT1 ablation enhances CD8+T cell cytotoxicity and synergizes with anti-PD1 immunotherapy in HCC. (Ma H, et al. Hepatology)
This research is significant not only for discovering SOAT1, a bifunctional target, but also for providing strong evidence for the repurposing of existing drugs. Avacillin, originally used to treat atherosclerosis, has now been shown to target SOAT1 in the treatment of liver cancer, significantly shortening the clinical translation cycle. For liver cancer patients, the future combination of "SOAT1 inhibitor + PD-1 inhibitor" may simultaneously address the two major challenges of tumor metabolic dependence and immune escape, offering new hope for overcoming drug resistance in liver cancer treatment and improving patient prognosis.
Reference
Ma H, et al. Targeting sterol O-acyltransferase 1 rewires fatty acid metabolism and uncovers immune vulnerability in hepatocellular carcinoma. Hepatology, 10.1097.