Enhancing anti-tumor immunity and immunotherapy efficacy through the downregulation of Acetyl-CoA carboxylase alpha in cancer cells

Abstract

Cancer immunotherapy has revolutionized treatment for many cancers by harnessing the immune system’s ability to recognize and eliminate tumor cells. Among these therapies, immune checkpoint inhibitors (ICIs) have shown significant promise in clinical trials. However, the development of resistance to ICIs remains a major obstacle. In this context, the role of Acetyl-CoA carboxylase alpha (ACACA), an enzyme involved in fatty acid metabolism, in cancer progression and immune modulation remains underexplored. To investigate its impact, we utilized CRISPR-Cas9 to generate ACACA-knockdown (ACACA KD) cancer cells and examined their effects on tumor growth and immune responses. In vitro, ACACA KD cells displayed reduced proliferation and enhanced susceptibility to immune-mediated cytotoxicity. In vivo, ACACA KD tumors grew more slowly, showed greater infiltration of effector T cells and NK cells, and upregulated immune-related pathways. Moreover, combining anti-PD-1 therapy with ACACA knockdown resulted in improved antitumor efficacy. Our study highlights ACACA as a potential target for enhancing the effectiveness of cancer immunotherapy.