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

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. 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. TLR4 knockout markedly improved the efficacy of OXA in vivo, reducing tumor burden while simultaneously downregulating key inflammatory mediators and glycolytic markers. 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.