Interkingdom microbiome physiology in colorectal cancer: barrier dysfunction, immune-metabolic signaling, and therapeutic resistance.

Colorectal cancer develops within a physiologically altered intestinal ecosystem. Epithelial barrier disruption, chronic inflammatory signaling, immune remodeling, and metabolic rewiring reshape host-microbial interactions in this niche. Although most colorectal cancer microbiome reviews have emphasized bacterial taxa, the gut ecosystem is inherently multi-kingdom, comprising bacteria, fungi, bacteriophages, and other viral elements that interact with one another and with the host. In this review, we propose that the clinically relevant unit of the colorectal cancer microbiome is often not a single organism but a configured interkingdom whose functional output depends on local physiology. Throughout, we distinguish human observational associations from mechanisms demonstrated in experimental models and from prospectively validated clinical effects. We synthesize evidence linking the bacteriome, mycobiome, and phageome to colorectal carcinogenesis, immune modulation, metabolic signaling, and therapeutic response. We highlight context-dependent mechanisms, including the paradoxical effects of Fusobacterium nucleatum, fungal regulation of myeloid and inflammasome pathways, phage-mediated control of bacterial virulence, and cross-kingdom metabolic circuits involving butyrate, succinate, bile acids, lactate, and arginine. We further propose, as a conceptual framework requiring longitudinal validation, that therapeutic resistance may sometimes reflect a treatment-selected ecological state rather than the action of a single resistance-conferring microbe. Finally, we address the reproducibility challenges raised by low-biomass intratumoral microbiome studies and outline minimum methodological standards for future multi-kingdom investigations. A framework centered in physiology, attentive to contamination, and organized around interactions may improve biomarker development and support rational microbiome-directed strategies in colorectal cancer.