Phytochemicals remodel antitumor immunity via the "microbiota-metabolite-receptor" axis: focus on colorectal cancer and immunotherapy.

Colorectal cancer (CRC) is a malignancy with high mortality. Due to the suppressive state of the tumor immune microenvironment (TIME), approximately 95% of microsatellite-stable (MSS) or proficient mismatch repair (pMMR) cases exhibit poor responsiveness to immune checkpoint inhibitors (ICIs). According to research, immune cell function can be regulated by gut microbiota and their metabolites via receptor-mediated pathways. They act as critical extrinsic factors in modulating the TIME and enhancing the efficacy of ICIs. Therefore, we systematically summarize the immunological mechanisms mediated through gut-specific metabolites (short-chain fatty acids, secondary bile acids, indole derivatives) and their cognate receptors (GPR41/43, GPR109A, FXR, TGR5, AhR). We further discuss how phytochemicals, after microbial transformation, modulate immune cells via the "microbiota-metabolite-receptor" axis. Key examples of such compounds include polysaccharides, saponins (and triterpenes), polyphenols, and alkaloids, which influence cells like Tregs, Th17, and CD8⁺ T cells. Simultaneously, we analyze the different effects of CRC-specific microbiota and the interventional potential of phytochemicals, while evaluating synergistic treatment possibilities between CRC and ICIs, chemotherapy, anti-angiogenic therapy, and radiotherapy. We propose a verifiable framework for stratification mechanisms of "phytochemicals-microbiota-metabolites-receptors-immune system-TIME-ICIs", and emphasize its potential application in MSS CRC immunotherapy to provide novel insights for precision treatment of CRC.