Host and gut microbiota crosstalk: A new paradigm for colorectal cancer immunotherapy

Abstract

Although immunotherapy for colorectal cancer (CRC) has recently gained widespread attention, many patients continue to exhibit inherent or acquired resistance due to a lack of tumor-infiltrating lymphocytes and the poor immunogenicity of cancer cells within an immunosuppressive tumor microenvironment. Advances in high-throughput sequencing and bioinformatics have increasingly highlighted the role of the gut microbiome (GM) in modulating the quantity and phenotypes of innate and/or adaptive immune cells, thereby influencing CRC pathogenesis and the clinical response to immunotherapy. The GM maintains a symbiotic relationship with the host, contributes to protection against opportunistic pathogens, and supports intestinal homeostasis. Dysbiosis in GM composition and metabolite profiles drive uncontrolled inflammatory cascades, induces oxidative DNA damage, and promotes neoplastic progression. Furthermore, targeting GM populations, such as next-generation probiotics or dietary interventions, can enhance the prevalence of effector T cells in a “hot” immunogenic microenvironment, thereby ameliorating the efficacy of CRC immunotherapy, improving survival and potentially reducing toxicities in patients. This review briefly summarizes current findings and molecular mechanisms underlying host-GM mutualism under physiological and cancerous conditions, which may inform the development of novel strategies for CRC diagnosis, treatment, and prevention.

Keywords: Colorectal cancer; Gut microbiota; Immunotherapy; Immune cell; Tumor microenvironment

Core Tip: From birth onward, host health is closely linked to the delicate balance of ecological microbiota composition. The microbiota utilizes distinct enzymatic capabilities to metabolize nutrients and produce immunomodulatory byproducts that influence organ function and behavior. A strong and rapid association has been identified between gut microbiome dysbiosis, defined as a disruption in microbial load or diversity, colorectal cancer pathogenesis, and responsiveness to immunotherapy. Therefore, clarify the mechanism of gut microbiome dysbiosis and develop microbe-based intervention through health-oriented and adaptable mechanisms, such as oral probiotic administration, will become an indispensable component of colorectal cancer immunotherapy in the future.