Vitamin D, Gut Microbiota, and Cancer Immunotherapy—A Potentially Effective Crosstalk

Recent breakthroughs in cancer immunotherapy have shown remarkable success, yet treatment efficacy varies significantly among individuals. Emerging evidence highlights the gut microbiota as a key modulator of immunotherapy response, while vitamin D (VD), an immunomodulatory hormone, has garnered increasing attention for its potential interactions with gut microbiota and immunotherapy outcomes. However, the precise mechanisms and clinical applications of VD in this context remain controversial. This study systematically analyzed peer-reviewed evidence from PubMed, Scopus, Web of Science, PsycINFO, and MEDLINE (January 2000–May 2025) to investigate the complex interplay among VD, gut microbiota, and cancer immunotherapy. This review demonstrates that VD exerts dual immunomodulatory effects by directly activating immune cells through vitamin D receptor (VDR) signaling while simultaneously reshaping gut microbial composition to enhance antitumor immunity. Clinical data reveal paradoxical outcomes: optimal VD levels correlate with improved immunotherapy responses and reduced toxicity in some studies yet are associated with immunosuppression and poorer survival in others. The bidirectional VD–microbiota interaction further complicates this relationship: VD supplementation enriches beneficial bacteria, which reciprocally regulate VD metabolism and amplify immune responses, whereas excessive VD intake may disrupt this balance, leading to dysbiosis and compromised therapeutic efficacy. These findings underscore the need to elucidate VD’s dose-dependent and microbiota-mediated mechanisms to optimize its clinical application in immunotherapy regimens. Future research should prioritize mechanistic studies of VD’s immunoregulatory pathways, personalized strategies accounting for host–microbiota variability, and large-scale clinical trials to validate VD’s role as an adjuvant in precision immunotherapy.