Recent advancements and limitations of intestinal organoids for clinical applications.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide, and there has been a concerning rise in its incidence among younger populations. Although there have been significant advances in molecular characterization, translating research findings into effective therapeutic strategies for CRC management remains suboptimal. This challenge is largely attributed to the limitations of conventional preclinical models, such as two-dimensional or patient-derived tumor xenograft (PDX), which fail to recapitulate the complexity and heterogeneity of CRC tissues. Intestinal organoids, derived from adult or pluripotent stem cells, have emerged as transformative tools to address the current limitations by mimicking the structural, genetic, and functional characteristics of native intestinal tissue in a three-dimensional culture environment. These organoids preserve patient-specific genomic features, allowing long-term growth, and serve as a more physiologically relevant model for studying CRC initiation, progression and drug resistance mechanisms. Furthermore, the integration of organoids with CRISPR/Cas9 genome editing, high-throughput drug screening, and multi-omics technologies has greatly enhanced their utility in personalized medicine and drug discovery. However, several unsolved challenges remain with the organoid model, such as culturing variability, a lack of protocol standardization, and an incomplete representation of the tumor microenvironment, particularly immune and stromal cells. This review offers a critical and comprehensive overview of intestinal organoid technologies in CRC research, identifies major knowledge gaps, and highlights emerging strategies to enhance their clinical application. The study aims to provide future directions that could significantly enhance precision oncology and ultimately improve therapeutic outcomes for CRC patients.