Targeting Microbiome Metabolites: Reshaping Immunotherapy and Clinical Management Strategies for Colorectal Cancer

Abstract

The pathogenesis of colorectal cancer (CRC) is closely associated with gut microbial metabolites, which exert crucial regulatory effects within the tumor immune microenvironment. These metabolites play a dual role in CRC immunity: certain metabolites promote tumor progression by inducing chronic inflammation, recruiting myeloid‐derived suppressor cells, and suppressing CD8 + T cell function; while others, such as short‐chain fatty acids and tryptophan metabolites, enhance anti‐tumor immunity and improve the efficacy of immune checkpoint inhibitors (ICBs). This paper systematically explores intervention strategies targeting this mechanism, including probiotics, prebiotics, metabolite adjuvants, and their combination with immunotherapy to overcome ICB resistance. Furthermore, the analysis of specific metabolites (e.g., cholic acid derivatives) and microbial signatures (e.g., enrichment of F. nucleatum ) has been identified as a potential avenue for the development of novel non‐invasive biomarkers, which could facilitate early screening and differential diagnosis. Notwithstanding the challenges encountered in the clinical translation of these technologies, the integration of multi‐omics and artificial intelligence with the immunoregulatory mechanisms and diagnostic potential of metabolites holds great promise for advancing precision medicine in the comprehensive management of CRC. It is becoming increasingly evident that metabolites play a pivotal role in the regulation of the tumor immune microenvironment. Gut microbiota metabolites have been shown to actively shape an immunosuppressive microenvironment by recruiting myeloid suppressor cells, modulating macrophage polarization, and depleting key amino acids essential for immunity. This process, therefore, promotes immune evasion in colorectal cancer. As demonstrated in the relevant literature, there is a direct correlation between the presence of harmful metabolites and the suppression of antitumour immune responses. For instance, succinate produced by F. nucleatum has been shown to inhibit the cGAS‐STING pathway, thereby reducing tumor infiltration by effector T cells. Furthermore, secondary bile acids have been observed to directly attenuate CD8 + T cell function, resulting in resistance to immunotherapy. The efficacy of immune checkpoint blockade is enhanced by beneficial metabolites. Probiotic‐derived metabolites (e.g., butyrate, inosine, and indole‐3‐propionic acid) have the capacity to reverse T‐cell exhaustion through epigenetic reprogramming and activation of immune signaling pathways, thereby significantly boosting the efficacy of PD‐1/CTLA‐4 inhibitors in colorectal cancer. Metabolites have been shown to modulate specific immune cell functions with a high degree of precision. Distinct metabolites have been observed to target particular immune cell subpopulations, with 4‐hydroxyphenylacetic acid, for example, having been shown to drive the aggregation of polymorphonuclear myeloid suppressor cells. Furthermore, tryptophan metabolites have been demonstrated to regulate regulatory T cells and cytotoxic T cells via the aromatic hydrocarbon receptor axis, thereby finely tuning immune responses. The role of probiotic metabolites as natural “immune adjuvants” is a subject of considerable interest. Metabolites from specific bacterial strains have been shown to activate dendritic cells, enhance the function of CD8 + T cells and natural killer (NK) cells, or induce M1 macrophage polarization. This, in turn, can systemically enhance anti‐tumor immune surveillance. Metabolites have been shown to have dual potential as diagnostic markers and therapeutic targets. The microbial metabolite profiles found in faeces or blood, for example, levels of butyrate, bile acids, and succinate, serve not only as non‐invasive diagnostic indicators but also predict responses to immunotherapy. This provides crucial insights for the early detection of colorectal cancer and combination strategies for precision immunotherapy.