ACAA2 was a predictor for the prognosis and immunotherapy response of hepatocellular carcinoma

Abstract Background Immunotherapy is the first-line treatment for advanced hepatocellular carcinoma (HCC). However, immunotherapy benefits are limited in certain patients. Therefore, identifying effective biomarkers is important for the efficient use of immunotherapy. In the present study, acetyl-CoA acyltransferase 2 (ACAA2), which was decreased during HCC initiation, was identified as a gene of interest. Methods In this study, we aimed to explore the role of ACAA2 in the progression of HCC and the link between ACAA2 and tumor microenvironment. Bulk RNA data and single-cell RNA data were acquired from the Cancer Genome Atlas and Gene Expression Omnibus. Both in vitro and in vivo studies were used to determine the effect of ACAA2 on the progression of HCC, and RNA sequencing analysis was performed to explore the mechanism. Results The patient with low ACAA2 level had an immunosuppressive microenvironment in the HCC and could be poor response to immunotherapy. Decreased ACAA2 facilitated HCC proliferation and metastasis by activating the nuclear factor-κB (NFκB) signaling pathway. And increased CXCL1 induced by NFκB signaling pathway was responsible for low level of ACAA2 related immune suppression microenvironment. Furthermore, the expression of ACAA2 in immune cells, CD4+TCF7+T, CD4+FOXP3+T, CD8+GZMK+T, and CD8+KLRD1+T cells, was inversely correlated with the composition of CD8+PDCD1+T cells in HCC. This effect may be due to the CCL5-CCRs and HLA-E-KLRCs ligand-receptor networks. Conclusions ACAA2 was a favorable indicator for the prognosis of HCC and an ideal biomarker for immunotherapy.