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Pathophysiology of colitis-associated colorectal cancer

Nature Reviews Gastroenterology & Hepatology (2026)Cite this article

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Abstract

Colitis-associated colorectal cancer (caCRC) is a subset of lower gastrointestinal tract malignancies that occurs in patients with inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn’s disease. The global prevalence of IBD is increasing, putting more individuals at risk of developing caCRC. The pathophysiological mechanisms that underlie the initiation and growth of caCRC remain to be fully elucidated. Nevertheless, studies have provided novel insights into the pathophysiology of caCRC, underscoring the distinguishing characteristics of caCRC compared with sporadic forms of CRC. In this Review, we describe the key mechanisms that drive caCRC. Starting from a clinical perspective and highlighting key features of the tumour epithelium, we discuss typical caCRC-related characteristics among subtypes of CRC, with a particular focus on the role of stromal cells in the tumour microenvironment. In addition, we review the contributions of immune cells to tumour control versus tumour promotion, and how signals from the gut microbiome might influence tumour development in caCRC. We also discuss various aspects of the pathophysiological heterogeneity of caCRC. Finally, we outline potential implications for therapy, and how these findings could be translated into future strategies of personalized medicine targeting caCRC.

Key points

  • Colitis-associated colorectal cancer (caCRC) remains — despite increased awareness and improved inflammatory bowel disease (IBD) therapies — a medical challenge, with rising numbers of people at risk globally.

  • Epithelial barrier disruption and chronic colitis in IBD accelerates epithelial ageing and positively selects for mutations related to IL-17/NF-κB signalling, which are negatively selected for during later tumour development.

  • Key features of caCRC include rapid tumour development, early inactivation of p53 during the malignant transformation of the epithelium, and promotion of mesenchymal subtype tumours.

  • The tumour microenvironment is shaped by tumour-associated innate and adaptive immune cells, cancer-associated fibroblasts and dysbiosis, all of which make critical contributions to caCRC.

  • Emerging data might lead to new strategies for disease prevention and personalized therapy targeting the microbiome, tumour epithelia, immune cell populations and the mesenchymal stroma.

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Fig. 1: Epithelial transformation in sporadic and colitis-associated colorectal cancer.
Fig. 2: Key cellular players in colitis-associated tumorigenesis.

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Data availability

The results presented in Supplementary Tables 2 and 3 were obtained with the assistance of cBioportal. The data are available upon request.

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Acknowledgements

The authors were supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation): TRR417 (540805631) to C.N. (P05) and M.F.N. (P09); NE1927/3-1 (539236816) to C.N.; TRR241 (375876048) to C.N. (A08) and M.F.N. (C04). Additional funding was provided by the Interdisciplinary Centre for Clinical Research (IZKF) Erlangen at Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg to C.N. (A97).

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  1. Universitätsklinikum Erlangen, First Department of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Clemens Neufert & Markus F. Neurath

  2. Universitätsklinikum Erlangen, Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany

    Clemens Neufert & Markus F. Neurath

  3. Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany

    Clemens Neufert & Markus F. Neurath

  4. Bavarian Cancer Research Center (BZKF), Erlangen, Germany

    Clemens Neufert & Markus F. Neurath

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Neufert, C., Neurath, M.F. Pathophysiology of colitis-associated colorectal cancer. Nat Rev Gastroenterol Hepatol (2026). https://doi.org/10.1038/s41575-026-01197-6

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