ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer
Sophie O’Keefe, Qiwei Wang
Sophie O’Keefe, Qiwei Wang
Published April 1, 2025
Citation Information: J Clin Invest. 2025;135(7):e191094. https://doi.org/10.1172/JCI191094.
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ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer

Abstract

Non–small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.

Authors

Sophie O’Keefe, Qiwei Wang

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Figure 1

Acetyl-CoA acetyltransferase 1 functions as a metabolic regulator of tertiary lymphoid structures in non–small cell lung cancer.

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Acetyl-CoA acetyltransferase 1 functions as a metabolic regulator of ter...
Tumor cell–intrinsic Acetyl-CoA acetyltransferase 1 (ACAT1) interacts with succinyl-CoA, driving hypersuccinylation at lysines (Ksucc) of mitochondrial proteins, which enhances intratumoral reactive oxygen species (ROS). This oxidative stress suppresses B cells, thereby inhibiting the formation of tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). NSCLC, non–small cell lung cancer; DC, dendritic cell.