Inhibition of TLR4 enhances oxaliplatin chemotherapy sensitivity in esophageal squamous cell carcinoma by suppressing inflammation and glycolysis.

BACKGROUND: Oxaliplatin (OXA) has become a key chemotherapeutic agent in the treatment of esophageal squamous cell carcinoma (ESCC). Toll-like receptor 4 (TLR4) is frequently upregulated in OXA-treated tumors, yet its role in regulating OXA sensitivity in ESCC remains unclear. This study suggests that TLR4 acts as a critical regulator of OXA responsiveness through dual modulation of NF-κB p65-driven inflammation and HIF-1α/GLUT1-mediated glycolysis. METHODS: Using ESCC cell lines and a 4-nitroquinoline 1-oxide (4-NQO)-induced murine ESCC model, we demonstrated that OXA upregulates TLR4 and its adaptor protein MYD88, thereby stimulating inflammatory cytokine production and activating glycolytic enzymes. Pharmacological inhibition or shRNA-mediated knockdown of TLR4 significantly enhanced the suppressive effects of OXA on ESCC proliferation, migration, and invasion in vitro. RESULTS: TLR4 knockout markedly improved the efficacy of OXA in vivo, reducing tumor burden while simultaneously downregulating key inflammatory mediators and glycolytic markers. CONCLUSIONS: These findings indicate that TLR4 inhibition enhances OXA’s chemotherapeutic effects by attenuating both inflammation and glycolytic metabolism. Our results support TLR4 signaling as a pivotal modulator of OXA sensitivity in ESCC and propose TLR4 targeting as a promising strategy for improving OXA-based chemotherapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12876-026-04663-2.