Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING
Blake R. Heath, Wang Gong, Hülya F. Taner, Luke J. 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 L. Lei
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.