Microbiota-Immune Crosstalk in Colorectal Cancer: Mechanisms, Metabolism, and Therapeutic Opportunities
DOI:
https://doi.org/10.66505/cbtt.v1i2.39Keywords:
microsatellite-stable colorectal cancer, immune checkpoint blockade, tumor microenvironment, immunometabolism, gut microbiome, metabolic reprogramming, microbial metabolites, immunotherapy resistanceAbstract
Microsatellite-stable (MSS) colorectal cancer (CRC) makes up most CRC cases but remains mostly resistant to immune checkpoint blockade (ICB), unlike the durable responses seen in microsatellite instability–high tumors. Increasing evidence indicates that resistance in MSS CRC stems not only from a lack of immune cells but also from complex constraints imposed by the tumor environment. Here, we review recent progress and introduce an immunometabolic barrier model in which tumor metabolic reprogramming, gut microbial imbalance, and immune suppression create mutually reinforcing resistance circuits. Processes like aerobic glycolysis, hypoxia, and nutrient competition produce lactate-rich, glucose-poor areas that impair cytotoxic T and NK cell activity while promoting regulatory T cells and suppressive myeloid cells. Meanwhile, CRC-related microbial imbalance damages barrier integrity and alters metabolite signaling, thereby enhancing inflammatory and inhibitory pathways, including adenosine and kynurenine–aryl hydrocarbon receptor signaling. These combined mechanisms lead to a metabolically restricted and immunologically “cold” tumor microenvironment, reducing the effectiveness of ICB alone. We believe that overcoming MSS resistance will require reprogramming the entire ecosystem by combining immunotherapy with metabolic and microbiome-targeted strategies guided by spatial and multi-omic biomarkers. Therefore, MSS CRC should be seen not just as a genetic subtype but as a dynamic state of immune resistance within the tumor ecosystem.
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