Vitamin D, Gut Microbiota and Cancer Immunotherapy-a Potentially Effective Crosstalk

Cancer immunotherapy has emerged as a revolutionary approach that harnesses the immune system to combat malignancies. While compelling evidence demonstrates that gut microbiota critically influences treatment efficacy through tumor microenvironment modulation, the role of vitamin D (VD) remains controversial yet promising. VD exerts dual immunomodulatory effects: it activates immune cells via vitamin D receptor (VDR) signaling while simultaneously shaping gut microbial composition to enhance antitumor immunity potentially. Clinical data present conflicting results - optimal VD levels correlate with improved immunotherapy response and reduced toxicity in some studies, yet paradoxically associate with immunosuppression and even poorer survival outcomes in others. While VD generally suppresses pro-inflammatory Th17/IL-17 pathways, emerging evidence reveals context-dependent Th17 activation that may promote tumor metastasis in specific populations. These contradictory findings underscore the urgent need to clarify VD's complex dose-dependent and microbiome-mediated immunoregulatory mechanisms. Future investigations should prioritize resolving these controversies to establish precise clinical applications of VD in immunotherapy regimens.