The role of intratumoral microbiome in the occurrence, proliferation, metastasis of colorectal cancer and its underlying therapeutic strategies

Abstract

Colorectal cancer (CRC), a leading cause of cancer mortality globally, is shaped by dynamic interactions between intratumoral microbiota and the tumor microenvironment (TME). Emerging evidence highlights the critical role of intratumoral bacteria, fungi, and viruses, such as Fusobacterium nucleatum and genotoxic Escherichia coli, in driving carcinogenesis through DNA damage, immune evasion, and metabolic reprogramming. While their origins remain debated, hypotheses include mucosal barrier penetration, migration from adjacent tissues, hematogenous dissemination, and co-metastasis with tumor cells. Spatial profiling reveals non-randomized microbial distribution within immunosuppressive TME niches characterized by reduced T-cell infiltration and enriched immunosuppressive molecules. Mechanistically, microbiota-derived metabolites (e.g., butyrate) and genotoxins (e.g., colibactin) modulate host pathways, promote epithelial DNA damage, polarize immune cells (e.g., M2-like macrophages, Tregs), and collectively, these contribute to fostering tumor progression. Conversely, microbial peptides or STING pathway activation by commensals like Bifidobacterium may enhance antitumor immunity. Intratumoral microbiota significantly influences therapeutic outcomes: F. nucleatum induces chemoresistance via autophagy, while Gammaproteobacteria inactivate gemcitabine. Immunotherapy responses are similarly modulated, with microbiota either amplifying antitumor T-cell activity or suppressing immunity through cytokine-mediated pathways. Innovative strategies, including engineered probiotics, bacterial vectors for drug delivery, and nanotechnology-enabled microbial modulation (e.g., functionalized nanoparticles, biomaterial carriers), aim to exploit these interactions. However, challenges such as low microbial biomass, contamination risks, and interpatient heterogeneity complicate translational efforts. Multi-omics and spatial-profiling technologies offer promise in deciphering microbial-immune-metabolic networks, guiding personalized therapies. Future research must address the biocompatibility of microbial-nanotech hybrids and validate intratumoral microbiota as biomarkers or therapeutic targets. Bridging gut and tumor microbiome studies could unlock novel CRC management strategies, emphasizing the dual role of microbiota as oncogenic drivers and therapeutic allies in precision oncology.

Keywords: Colorectal cancer; Immunotherapy; Intratumoral microbiome; Therapeutic strategies.