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Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING
Blake R Heath1, Wang Gong2, Hülya F Taner3
1Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA.
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.
Insights
Obesity hinders anti-cancer immunity by promoting suppressive myeloid cells and inhibiting the STING-IFN-I pathway via saturated fatty acids, worsening head and neck squamous cell carcinoma progression.
Area of Science:
- Immunology
- Oncology
- Metabolism
Background:
- Oncogenes promote immune escape in cancers like head and neck squamous cell carcinomas (HNSCCs) by destabilizing STING.
- HNSCC exhibits resistance to STING stimulation despite abundant tumor-infiltrating myeloid cells.
- Obesity is linked to an altered tumor microenvironment that may impact cancer immunity.
Purpose of the Study:
- To investigate how saturated fatty acids in the tumor microenvironment affect STING pathway activation and anti-tumor immunity in HNSCC.
- To elucidate the role of obesity-induced changes in myeloid cells and T cells in HNSCC immune evasion.
Main Methods:
- Single-cell analysis of tumor microenvironments in obese and lean models.
- Assessment of STING-IFN-I pathway activation in HNSCC cells treated with saturated and unsaturated fatty acids.
- Evaluation of myeloid cell suppressive function and T cell activation.
- In vivo studies using obese and lean hosts with HNSCC xenografts treated with STING agonists.
Main Results:
- Obesity creates an interferon-I (IFN-I)-deprived tumor microenvironment characterized by expanded suppressive myeloid cells and reduced effector T cells.
- Saturated fatty acids, abundant in obesity, potently inhibit the STING-IFN-I pathway in HNSCC cells, while unsaturated fatty acids do not.
- Myeloid cells from obese mice show impaired STING responses and increased T cell suppression.
- Obese hosts exhibit greater tumor burden and diminished responsiveness to STING agonists.
- Saturated fatty acids induce NLRC3 expression, which suppresses the STING pathway; NLRC3 depletion reverses these effects.
Conclusions:
- Saturated fatty acids in obesity-induced microenvironments dampen STING pathway activation in HNSCC, promoting immune evasion.
- NLRC3 acts as a key mediator, translating saturated fatty acid signals into STING pathway inhibition.
- Targeting NLRC3 or modulating fatty acid metabolism could restore STING-mediated anti-tumor immunity in obese HNSCC patients.
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