A newly published comprehensive review provides extensive evidence supporting vitamin D's potentially significant role in colorectal cancer prevention through multiple immunological mechanisms and inflammatory pathways. The report consolidated findings from 50 clinically relevant cohort studies comprising over 1.3 million participants.

“Vitamin D plays a crucial role in the regulation of the immune system, with immunomodulatory effects that are key in the prevention of colorectal cancer (CRC),” wrote Hungarian researchers from Semmelweis University, led by corresponding author János Tamás Varga, MD, in Nutrients.

Investigators analyzed prospective studies published through January 2025, focusing on vitamin D’s protective effects against CRC, which remains a significant global health burden—approximately 1.2 million new cases are diagnosed annually.

Key Immunological Mechanisms

The review details specific pathways through which vitamin D may exert anticancer effects:

• Immune cell regulation: Vitamin D acts on T-lymphocytes, B-lymphocytes, and macrophages—all of which express vitamin D receptors and can convert vitamin D to its active form, 1,25(OH)₂D.

• Anti-inflammatory effects: It suppresses pro-inflammatory T-helper cells, notably Th1 and Th17, which contribute to CRC progression.

• Cytokine modulation: 1,25(OH)₂D downregulates IL-6, IL-12, and TNF-α and promotes IL-4, IL-5, IL-10, and IL-13 production.

• Dendritic cell regulation: It suppresses monocyte differentiation into dendritic cells, reducing T-cell activation.

• Macrophage enhancement: Vitamin D enhances chemotaxis and phagocytosis, boosting immune defense against malignant cells.

Clinical Evidence and Mechanisms

The authors highlighted several tumor-suppressing mechanisms:

• “Calcitriol induces G1 cell cycle arrest, reducing CRC cell proliferation, and restoring sensitivity to tumor suppressors like TGF-β," they noted.

• Vitamin D regulates the hyperactivated Wnt/β-catenin pathway in CRC, lowering β-catenin activity and increasing E-cadherin expression, thus improving cell-cell adhesion.

• Additional mechanisms include antiangiogenesis via VEGF and NF-κB suppression, pro-apoptotic activity through BAX and BAK upregulation, and reduction of CRC-related inflammation.

Novel Mechanisms

The review authors presents ferroptosis as a novel antiancer mechanism, whereby vitamin D—specifically, 1,25(OH)₂D—induces ferroptosis in CRC stem cells by regulating SLC7A11 and promoting reactive oxygen species generation.

Vitamin D may also exert anti-ancer effects by activating SIRT1, a gene involved in DNA repair, aging, and cancer suppression. SIRT1 expression and vitamin D receptor activation are interlinked and may modulate CRC progression via epigenetic pathways.

Clinical and Epidemiological Findings

Meta-analyses cited in the review found that higher serum 25(OH)D levels are associated with a 39% lower CRC risk in case-control studies and 20% lower risk in prospective cohort studies.

The authors also detailed results from the SUNSHINE trial, in which patients receiving high-dose vitamin D (4000 IU/day following an 8,000-IU loading dose) experienced a 2-month longer progression-free survival compared with those receiving 400 IU/day.

Supplementation and Dietary Considerations

“To reduce the risk of CRC, it is crucial to follow a healthy, nutrient-dense diet that provides sufficient vitamin D, as well as foods rich in calcium and fiber,” the authors advised.

They emphasized that Western dietary patterns high in processed foods, red meat, and added sugars contribute to inflammation and worsen vitamin D deficiency.

The 2022 Hungarian Consensus Recommendation on the Role of Vitamin D in the Prevention and Treatment of Diseases advises that adults should take 2,000 IU of vitamin D daily, with an upper safe limit of 4,000 IU/day, and that supplementation may be necessary in winter or for at-risk populations.

Conclusion

This extensive review affirms the multifaceted role of vitamin D in CRC prevention—through direct antitumor effects, modulation of immune and inflammatory responses, ferroptosis induction, and microbiome support. While the mechanistic and observational evidence is strong, further randomized clinical trials are needed to define optimal supplementation protocols and integrate vitamin D into personalized oncology care.

The authors declared no conflicts of interest.

Source: Nutrients