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Highlights

•Obesity establishes an IFN-I-deprived tumor microenvironment and increases tumor burden

•Myeloid cells from obese hosts are desensitized to STING stimulation

•Saturated fatty acids inhibit the STING pathway by inducing NLRC3

• NLRC3 inhibits the immunogenicity of HNSCC in an IFN-I-dependent fashion

Summary

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.

So, for the layman... Obesity makes some cancer worse and /or more prevalent? Or harder to treat? What's STING stimulation?

Too bad there are no health benefits to being obese! I love cake and ice cream. And I eat them anyway- with some guilt.

The study suggests that saturated fats inhibit the STING pathway, which is a way for your body to recognize and fight bad cells. This means that saturated fats can make it harder for your body to fight off bad cells like tumors.

In contrast, the study found that unsaturated fats did not have the same effect on the STING pathway. This suggests that unsaturated fats may not be as harmful to your body's ability to fight off bad cells like tumors.

The STING pathway (STimulator of INterferon Genes pathway) is a part of our immune system that helps our body to recognize and fight off invading viruses, bacteria, and cancer cells.

When our body detects the presence of these bad cells, it triggers the STING pathway, which leads to the production of a type of protein called interferon. Interferon helps to activate other immune cells in our body, such as T cells and natural killer cells, which then work together to destroy the invading cells.

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