Targeting the LPS-STING axis: neomycin restores STING-mediated anti-tumor immune suppression and inhibits tumor growth.

INTRODUCTION: The interplay between microbial metabolites and host immunity within the tumor microenvironment (TME) critically modulates anti-tumor immune responses. The role of Gram-negative bacteria and their cell wall component lipopolysaccharide (LPS) in this context warrants further investigation. METHODS: We assessed the impact of low-dose LPS pretreatment on macrophage function by measuring type I interferon (IFN-β) secretion in response to tumor cell debris. Mechanistic insights were gained by analyzing endogenous signaling pathways in macrophages. The therapeutic potential of targeting LPS was evaluated in melanoma-bearing mice treated with neomycin, alone or in combination with STING agonists. RESULTS: Low-dose LPS pretreatment significantly suppressed IFN-β secretion by macrophages, indicating LPS-mediated immunosuppression. Mechanistically, LPS disrupted endogenous signaling pathways, blunting the ability of macrophages to sense tumor-derived damage signals. In vivo, neomycin treatment markedly inhibited melanoma growth and synergized with STING agonists. DISCUSSION: Our findings demonstrate that elevated LPS in the TME inhibits anti-tumor innate immunity by impairing macrophage function. The combination of LPS modulation via neomycin with innate immune activation via STING agonists presents a potential strategy to enhance tumor immunotherapy.