Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.

Abstract

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.

• Authors: Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 4 Pg. 112303 (04 25 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36952341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Fatty Acids
• Interferon Type I

Topics

• Mice
• Animals
• Squamous Cell Carcinoma of Head and Neck
• Fatty Acids
• Interferon Type I (metabolism)
• Myeloid Cells (metabolism)
• Head and Neck Neoplasms
• Tumor Microenvironment