Unveiling the Anti-tumor Actions and Therapeutic Potential of Calcitriol in Colorectal Cancer

Calcitriol (1,25-dihydroxyvitamin D₃), the active form of vitamin D, signals through the vitamin D receptor (VDR) and has been linked to colorectal cancer (CRC) risk and progression. This review summarizes current evidence on calcitriol/VDR actions relevant to CRC prevention and therapy. A structured literature search of PubMed, Scopus, and Web of Science was conducted through December 2025 for studies on calcitriol, VDR, and CRC, including mechanistic, preclinical, epidemiological, and clinical trial reports. Evidence was synthesized narratively with an emphasis on pathways connecting epithelial biology, inflammation, and the tumor microenvironment. Across model systems and patient studies, calcitriol/VDR signaling is associated with reduced proliferation, enhanced differentiation and apoptosis, and repression of oncogenic programs including Wnt/beta catenin and MYC-driven transcription. Calcitriol can also shape the tumor immune milieu by limiting pro-inflammatory signaling (for example, NF-κB, COX 2, IL-6 and IL-8), supporting epithelial tight junctions, and modulating the microbiome and bile acid metabolism, which together may enhance immune surveillance and reduce tumor-permissive inflammation. Evidence from supplementation trials is mixed, suggesting heterogeneity in baseline vitamin D status, tumor stage and VDR pathway context. Calcitriol engages convergent epithelial and immune mechanisms that plausibly limit CRC initiation and progression, but optimal patient selection and dosing strategies remain unresolved. Future trials integrating molecular biomarkers and VDR-responsive gene signatures are needed to define when vitamin D-based interventions can provide meaningful benefit in CRC.