Inflammatory bowel disease-associated colorectal cancer (IBD-CRC) represents a distinct clinical and molecular entity characterized by long-standing inflammation and a unique "dysplasia-carcinoma" sequence. While epithelial genetic alterations are well-documented, the role of the mesenchymal stroma as a dynamic driver of malignant transformation remains underappreciated. In this review, we propose a conceptual framework where intestinal fibroblasts contribute significantly to niche construction as key components of the Tumor Microenvironment (TME) architecture. These cells are not merely passive scaffolds but dynamically co-evolve with the epithelium and immune compartment, transitioning into active orchestrators of the pre-malignant niche. We highlight the emerging concept of "stromal inflammatory memory," which is hypothesized to be encoded through stable epigenetic imprinting and persistent metabolic reprogramming, characterized by a PFKFB3-mediated glycolytic shift. This metabolic priming sustains a pro-tumorigenic environment even during clinical remission. We further delineate how the loss of apical polarity regulators, such as aPKC, triggers a cascade of epithelial-stromal crosstalk involving chronic microbial sensing and hyaluronan-driven signaling. This co-evolution leads to the diversification of cancer-associated fibroblast (CAF) subsets, including inflammatory (iCAF), myofibroblastic (myCAF), and antigen-presenting (apCAF) populations. These subsets collectively orchestrate immune evasion via T-cell exhaustion and physical immune exclusion. Finally, we discuss the clinical implications of the "Reverse Warburg Effect" and exosome-mediated chemoresistance. We emphasize that effective therapeutic strategies must transcend epithelial-centric models to target the stromal axis. By integrating recent advances in single-cell and spatial transcriptomics, we identify novel opportunities for "stromal reprogramming" through metabolic, epigenetic, and senomorphic interventions to prevent and treat IBD-CRC.
Naito et al. (Tue,) studied this question.