Multidimensional regulation of the microbe-TLR4 signaling Axis in colorectal cancer: From molecular mechanisms to microbe-targeted therapies

Abstract

Colorectal cancer (CRC), the third most common cancer globally, arises from complex interactions between genetic predisposition, environmental factors, and gut microbiota dysbiosis. This review systematically analyzes the multidimensional regulatory mechanisms of the microbe-TLR4 signaling axis in CRC, including key pathways such as TLR4/NF-κB, MAPK, TRIF/IRF3, Keap1/NRF2/CYP2J2, and ceramide/β-catenin/SOAT1. These pathways drive tumor progression through metabolic reprogramming, immune modulation, and genotoxic effects. Therapeutic strategies targeting this axis encompass natural compounds (e.g., terpenoids, polysaccharides, saponins), traditional Chinese medicine formulas (e.g., Ganluyin, Xiao-Chai-Hu-Tang), microbiota therapies (probiotics, engineered bacteria, oncolytic viruses), and dietary and metabolic regulation (dietary fiber, methionine), exerting anti-tumor effects by inhibiting excessive TLR4 activation, repairing intestinal barriers, and regulating microbial balance. The review highlights challenges such as the complexity of signaling pathways, precise microbiota modulation, and drug delivery. At the same time, emerging technologies like single-cell multi-omics and artificial intelligence prediction models offer new directions for precision interventions. Targeting the microbe-TLR4 axis holds promise as an innovative strategy for CRC treatment.