Abstract
Endotoxin tolerance (ET) is an immunological state in which repeated exposure to endotoxins such as lipopolysaccharide (LPS) leads to reprogramming of the immune system and a diminished inflammatory response. In this study, we used a murine model to explore the role of ET in breast cancer progression, hypothesizing that ET may foster a tumor-permissive immune environment. We compared endotoxin tolerant breast cancer-bearing mice (ETBC group) with non-endotoxin tolerant breast cancer-bearing controls (BC group). ETBC mice exhibit significantly faster tumor progression and earlier disease onset. Hematological analysis revealed reduced leukocyte counts in the ETBC group, indicating compromised immune cell recruitment. Additionally, ETBC mice showed decreased spleen weight relative to that in the BC group, further supporting systemic immune suppression. Gene expression profiling in both spleen and tumor tissues revealed marked immunological alterations in ETBC mice. In the spleen, there was notable downregulation of key pro-inflammatory cytokines, including interleukin (IL) 6 and interferon (IFN) γ. Conversely, genes associated with immune modulation and tumor progression such as IL-1β, inducible nitric oxide synthase (NOS2), cyclooxygenase (COX) 2, vascular endothelial growth factor (VEGF), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, IL-1β, NOS2, COX-2, IL-10, and VEGF were consistently upregulated in tumor tissues of ETBC mice. We conclude that ET not only impairs immune surveillance but also reshapes the tumor microenvironment in favor of cancer growth. This highlights the potential role of ET in oncology and suggests that its modulation could represent a novel avenue for therapeutic intervention.