The TLR4/MyD88 axis in cancer: divergent and convergent roles of NF-κB and NLRP3 inflammasome activation and therapeutic opportunities.

Abstract

The TLR4/MyD88 signaling axis serves as a central hub linking microbial- and damage-associated molecular patterns to oncogenic inflammation. Upon ligand engagement, MyD88 orchestrates two major downstream branches, including the canonical NF-κB pathway, which drives transcriptional programs for cell survival, proliferation, angiogenesis, and metastasis, and the NLRP3 inflammasome, which amplifies IL-1β/IL-18 release and pyroptosis. While these branches have been extensively studied individually, their integrated roles and crosstalk remain underexplored in cancer. Recent advances show that NF-κB provides the essential signal 1 for NLRP3 priming, yet the two pathways exert cell-type- and tumor-stage-dependent, sometimes opposing effects on tumor progression, therapy resistance, and anti-tumor immunity. We highlight cancer-type and cell-type specificity, microbiome influences, and emerging therapeutic opportunities targeting TLR4, NF-κB, and NLRP3 individually or in combination. This unified framework positions the TLR4/MyD88 axis as a high-value target for precision oncology and underscores the need for pathway-selective inhibitors to harness its divergent outputs.