Impact of vitamin D on the colon cancer immune microenvironment: results of a randomized clinical trial of preoperative vitamin D supplementation in patients with stage I-III colon cancer

Although vitamin D (VitD) exhibits anti-tumor activity in colorectal cancer (CRC) preclinically, its effects in the human tumor microenvironment (TME) remain unclear. We conducted a randomized, placebo-controlled trial of preoperative high-dose VitD supplementation in stage I-III colon cancer patients to assess its impact on the TME. Forty-two patients received either VitD3 (50,000 IU/day for 7 days, then 10,000 IU/day) or placebo before surgery. Spatial immune-profiling and assessment of VitD receptor (VDR) and CYP27B1 expression were performed on paired tumor samples from 24 patients. VitD significantly increased plasma 25-hydroxyvitamin D levels (P<0.001), increased CD3+CD8+ memory T cells (P=0.03), reduced CD3+CD4+FoxP3+ regulatory T cells (P=0.02) and spatially re-organized the TME, leading to greater T cell and tumor cell proximity. Post-treatment VDR expression was heterogeneous and decreased overall (P=0.02). Spatial transcriptomic profiling of post-treatment resections reflected predominantly repressive VDR activity. These findings support an immunomodulatory role for VitD, warranting further mechanistic investigation.