Mechanistic study of lipopolysaccharide-induced protection in macrophages against antitumor drugs

Cancer has become the leading cause of death, and chemotherapy remains the mainstay of treatment. However, chemotherapeutic agents are less selective and their cytotoxicity can damage immune cells, including macrophages, affecting patient survival. Lipopolysaccharide (LPS) in vivo elicits a range of immune responses and thus plays a role in the immune system. This study aimed to investigate the mechanism of the protective effect of LPS against macrophage damage caused by antitumor drugs. Here, we found that LPS protects macrophages from antitumor drug-induced damage, while no comparable protective effect was observed in tumor cells. There was no significant difference in cell viability after inhibition of Toll-like receptor 4 (TLR4) and caspase-11, canonical receptors for LPS. Given the central role of oxidative stress in antitumor drug-induced cytotoxicity, we investigated whether solute carrier (SLC) family-mediated amino acid transport contributes to the protective effects of LPS. qRT-PCR analysis showed that LPS significantly upregulated SLC3A2 and SLC7A11, two genes essential for the function of system Xc^- (the cystine/glutamate antiporter), which regulates glutathione (GSH) synthesis. Treatment of the ADR + LPS group with the system Xc^- inhibitor erastin or the ABCC1 inhibitor MK571 significantly reduced macrophage viability, decreased SLC7A11 expression, and lowered intracellular GSH levels. These results suggest that LPS may promote system Xc^--dependent GSH synthesis and is associated with ABCC1-mediated drug transport, thereby contributing to the protection of macrophages like RAW264.7 from drug-induced damage. This study elucidates LPS-mediated protective mechanisms and provides mechanistic insight that may help identify safer therapeutic strategies.