Colorectal cancer (CRC) remains a major global oncological challenge, largely because most microsatellite-stable (MSS) tumors exhibit intrinsic resistance to immune checkpoint blockade (ICB). Emerging evidence suggests that the gut microbiome and host circadian rhythm jointly regulate mucosal homeostasis; however, their dynamic integration-defined here as the circadian-microbiome-immune axis-remains incompletely understood in CRC. In this review, we synthesize preclinical findings and the limited available clinical evidence concerning this axis. Experimental studies using genetic and lifestyle-related models of circadian disruption indicate that clock dysfunction may impair the intestinal mucosal barrier and alter microbial composition, including depletion of beneficial taxa such as Lactobacillus. These changes have been associated with metabolic remodeling, including increased taurocholic acid (TCA), which has been shown in cell and animal models to activate the RasGRF1/MAPK/ERK pathway. Preclinical evidence further suggests that intestinal clock disruption may interact with Wnt signaling and chemokine networks, including CXCL5 and IL-17, thereby promoting the rhythmic recruitment of PD-L1-expressing myeloid-derived suppressor cells (MDSCs). On this basis, we propose the Temporal Immunosuppressive Shield (TIS) as a hypothesis-generating conceptual framework linking epithelial barrier dysfunction, microbial metabolic remodeling, and temporally gated myeloid-mediated suppression of cytotoxic CD8+ T cells. Because this integrated model has not yet been directly validated in human MSS CRC, it should not be regarded as an established biological mechanism. We also discuss the potential of biologically phase-aligned ICB and chemotherapy, conceptually termed chronoimmunotherapy, while emphasizing current challenges in circadian biomarker development, interindividual variability, and mouse-to-human translation. Overall, this review outlines a testable spatiotemporal framework and identifies the experimental and clinical studies required to evaluate its relevance to therapeutic resistance in CRC.
