Endotoxin Tolerance Creates Favourable Conditions for Cancer Development

SIMPLE SUMMARY: Macrophages, depending on their phenotype, can either destroy or stimulate cancer cells. Therefore, it is very important to identify the conditions under which they adopt a dangerous phenotype. Our study investigated the impact of endotoxin tolerance (ET) on macrophage behaviour and its role in cancer development. By utilizing in vitro models and diverse research methods, including examining conditioned medium effects on 3D cancer cell cultures and studying macrophage-cancer cell crosstalk, we discovered that ET-induced macrophage reprogramming leads to the release of factors that promote a cancer-favourable environment. Our findings highlight the dual nature of ET as a mechanism, potentially contributing to cancer progression. This work suggests that targeting ET could offer novel avenues for cancer prevention and treatment. To the best of our knowledge, our research group is the first to uncover this adaptive mechanism’s potential role in cancer development. ABSTRACT: Endotoxin tolerance (ET) is an adaptive phenomenon of the immune system that protects the host from clinical complications due to repeated exposure of the body to endotoxins such as lipopolysaccharide (LPS). Since ET is an immunosuppressive mechanism in which a significant reprogramming of macrophages is observed, we hypothesized that it could influence cancer development by modifying the tumour environment. This study aimed to explore whether ET influences cancer progression by altering the tumour microenvironment. Endotoxin-tolerant macrophages (Mo(ET)) were examined for their impact on breast and colon cancer cells via direct interaction and conditioned media exposure. We characterized cancer cell behaviour by viability, clonogenic potential, motility, scratch assays, and 3D spheroidal assays. Mo(ET)-derived factors increased cancer cell viability, motility, and clonogenicity, suggesting a conducive environment for cancer development. Remarkably, despite reduced TNFα and IL-6 levels, Mo(ET) exhibited M1 polarization. These findings uncover an ET-associated macrophage reprogramming that fosters a favourable context for cancer progression across diverse tumours. Targeting ET could emerge as a promising avenue for cancer therapy and prevention.