Vitamin D Receptor in Cancer: Biological Functions, Mechanistic Insights, and Clinical Relevance

Ming Liang,1,* Shengjie Yin,2,* Yisheng Dai,3,* Fan Xu,4 Bowen Chang,4 Siniša Volarević,5 Xiaobo Li,4 Di Wu,6 Zhiwei Li,3 Tianzhen Wang4 1Department of Infection, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China; 2Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng, People’s Republic of China; 3Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China; 4Department of Pathology, Harbin Medical University, Harbin, People’s Republic of China; 5Department of Molecular Medicine and Biotechnology, University of Rijeka Faculty of Medicine, Rijeka, Croatia; 6Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiwei Li, Email lizhiwei@hrbmu.edu.cn Tianzhen Wang, Email wtzpath@163.comAbstract: Vitamin D (VD) has been the focus of extensive clinical research, yet conclusions regarding its biological roles remain inconsistent. VD exerts its functions through the vitamin D receptor (VDR), a nuclear transcription factor that regulates the expression of VD3-responsive target genes. Notably, divergent findings across studies have been reported regarding VDR expression patterns and functional roles, underscoring the complexity of VDR in cancer biology. Whether this complexity interferes with VD’s biological activity-thereby contributing to the variable impacts of VD3 on cancer prevention and treatment-remains unclear. This review systematically addresses: (1) the association between VDR expression (assessed by immunohistochemistry) and cancer prognosis; (2) the roles and mechanisms of VDR in cancer; (3) the multi-level regulatory networks governing VDR expression and activity; and (4) the translational implications of VDR in cancer therapy. Elucidating the precise roles and mechanisms of VDR is critical for optimizing cancer treatment strategies and resolving conflicting clinical evidence.Keywords: vitamin D receptor, cancer, prognosis, function and mechanism, therapy