Divergent impact of endotoxin priming and endotoxin tolerance on macrophage responses to cancer cells

Endotoxin tolerance (ET) is an adaptive phenomenon that arises from the repeated exposure of immune cells, such as macrophages, to endotoxins like lipopolysaccharide (LPS). Initially, when macrophages are activated by LPS, they produce inflammatory mediators that drive the primary immune response. However, this response is significantly diminished during the establishment of ET, creating an immunosuppressive environment. This environment can facilitate the development and progression of malignant conditions, including cancer. Our research focused on the interactions between immune cells and the tumor microenvironment under ET conditions. Through comprehensive in vivo and in vitro studies employing various research techniques, we have demonstrated that interactions between endotoxin-tolerant macrophages (MoET) and cancer cells contribute to a pro-tumorigenic condition. Notably, we observed that MoET adapt a pro-tumorigenic, immunosuppressive M2 phenotype (CD163 expression). These macrophages involves distinct metabolic pathways, not depending solely on glycolysis and oxidative phosphorylation. Furthermore, our in vivo findings revealed macrophage infiltration within tumors under both ET and non-ET conditions, highlighting the suppressed immune landscape in the presence of ET. These findings suggest that ET plays a pivotal role in shaping tumor-associated immune responses and that targeting ET pathways could offer a novel and promising therapeutic approach for cancer treatment.