Human cathelicidin peptide LL-37 is encoded by the CAMP gene and plays a key role in innate immunity. It maintains intestinal homeostasis through antibacterial, immunomodulation, and tissue repair functions. This paper reviews the multiple functions of LL-37 in the intestinal-immune axis and its contribution to intestinal immune homeostasis. A large amount of evidence shows that the biological effect of LL-37 is highly dependent on the environmental background, and its effects vary with peptide concentration, receptor binding status, disease stage, and local microenvironment. This article reviews the latest findings of the dual role of LL-37 in inflammatory bowel disease (IBD) and colorectal cancer (CRC), and focuses on the conditional mechanism of the transformation of its activity from protective to pathogenic. We also discuss the interaction between LL-37 and intestinal microbiota, focusing on how microbial signals and host peptides can coordinate to regulate mucosal immunity. At the same time, this article examines the key obstacles to the therapeutic application of LL-37 and its clinical promotion: cytotoxicity, rapid degradation by proteases, and drug resistance. We have further explored new strategies to overcome these challenges in the near future, including peptide engineering, nanocarrier delivery systems, and combined therapy. These findings together position LL-37 at the intersection of intestinal immunity and microbial ecology, providing a theoretical basis for its therapeutic application in IBD, CRC and infectious colitis.
Keywords: Gut microbiota; Inflammatory bowel disease; LL‐37; antimicrobial peptides; colorectal cancer; gut–Immune Axis.
© 2026 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.