Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer.

Pancreatic cancer has a dismal prognosis, while its incidence is increasing. This is attributed, in part, to a profound desmoplastic and immunosuppressive tumor microenvironment associated with this cancer and resistance to current available therapies. Novel and effective intervention strategies are urgently needed to improve the outcomes of patients with pancreatic cancer. Vitamin D has pleiotropic functions beyond calcium-phosphate homeostasis and has been extensively studied both in the laboratory and clinic as a potential preventive agent or adjunct to standard therapies. Accumulating evidence from ecological, observational, and randomized controlled trials suggests that vitamin D has beneficial effects on risk, survival, and mortality in pancreatic cancer, although controversies still exist. Recent advances in demonstrating the important functions of vitamin D/vitamin D receptor (VDR) signaling in the regulation of stromal reprogramming, the microbiome, and immune response and the emergence of checkpoint immunotherapy provide opportunities for using vitamin D or its analogues as an adjunct for pancreatic cancer intervention. Many challenges lie ahead before the benefits of vitamin D can be fully realized in pancreatic cancer. These challenges include the need for randomized controlled trials of vitamin D to assess its impact on the risk and survival of pancreatic cancer, optimizing the timing and dosage of vitamin D or its analogues as an adjunct for pancreatic cancer intervention and elucidating the specific role of vitamin D/VDR signaling in the different stages of pancreatic cancer. Nevertheless, vitamin D holds great promise for reducing risk and improving outcomes of this disease.