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

## TL;DR

Blocking TLR4 improves oxaliplatin effectiveness in treating esophageal cancer by reducing inflammation and glycolysis.

## Contribution

TLR4 inhibition enhances oxaliplatin sensitivity in ESCC by suppressing inflammation and glycolytic metabolism.

## Key findings

- TLR4 inhibition significantly enhances oxaliplatin's anti-cancer effects in ESCC cell lines.
- TLR4 knockout in mice improves oxaliplatin efficacy by reducing tumor burden and glycolytic markers.
- TLR4 signaling modulates oxaliplatin sensitivity through NF-κB and HIF-1α pathways.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s12876-026-04663-2.