Watch Kirk Hamilton PAC’s Video Summary of This Interview Here
Professor János Tamás Varga, MD
Department of Pulmonology, Semmelweis University
1083 Budapest, Hungary
varga.janos.tamas@semmelweis.hu
Mónika Fekete, MD
Institute of Preventive Medicine and Public Health
Faculty of Medicine, Semmelweis University
1089 Budapest, Hungary
fekete.monika@semmelweis.hu
“Vitamin D and Colorectal Cancer Prevention: Immunological Mechanisms, Inflammatory Pathways, and Nutritional Implications,”
Nutrients. 2025 Apr 15;17(8):1351 (7/2025)
Kirk Hamilton: Can you please share with me your educational background and current position?
Dr. Mónika Fekete and Prof. János Tamás Varga: The authors of the study are affiliated with various faculties and research institutes of Semmelweis University, primarily working in preventive medicine, nutrition science, immunology, pulmonology, and cardiovascular medicine. Several authors hold medical degrees (MD) and PhDs, and currently serve as educators, researchers, or clinicians within different departments of Semmelweis University (e.g., Department of Preventive Medicine and Public Health, Heart and Vascular Clinic, Department of Rheumatology and Clinical Immunology, Department of Pulmonology). We also collaborate with the HUN-REN Energy Science Research Centre. The corresponding author of the article is Prof. János Varga, Professor at the Department of Pulmonology, Semmelweis University.
KH: What got you interested in studying the role of vitamin D in colorectal cancer prevention and treatment?
MF & JTV: Colorectal cancer (CRC) is one of the most common cancers and causes of cancer-related mortality worldwide. Therefore, research into preventive strategies is of high importance for public health and preventive medicine. The role of vitamin D has gained increasing attention not only for bone metabolism but also for its immunomodulatory and anti-inflammatory effects over the last decade.
Our research group was motivated by the observed epidemiological and clinical associations between vitamin D deficiency and CRC incidence. However, many underlying mechanisms remain unclear. We were particularly interested in exploring the immunological and inflammatory pathways involved, as they play key roles in carcinogenesis and could serve as targets for preventive strategies.
Furthermore, nutritional and lifestyle aspects of vitamin D — such as supplementation optimization and addressing population-wide deficiencies — are especially relevant for public health practice.
KH: What is the mechanism of how vitamin D adequacy may prevent colorectal cancer?
MF & JTV: Vitamin D, especially its active form calcitriol (1,25(OH)₂D₃), regulates multiple cellular processes critical in cancer prevention:
Cell differentiation and proliferation inhibition: Activation of the vitamin D receptor (VDR) promotes normal cell differentiation and inhibits excessive cell division, which is crucial in colorectal epithelial cells where dysregulated proliferation can lead to cancer.
Promotion of apoptosis: Calcitriol induces programmed cell death in damaged or transformed cells, eliminating potentially cancerous cells.
Modulation of inflammatory pathways: Vitamin D suppresses pro-inflammatory cytokines (e.g., IL-6, TNF-α) while promoting anti-inflammatory mediators (e.g., IL-10), which is important given the link between chronic inflammation (such as ulcerative colitis) and CRC risk.
Immunomodulation: Vitamin D balances innate and adaptive immunity, enhancing tumor-fighting cytotoxic T cells (CD8⁺) and reducing pro-tumor immune populations (e.g., Th17 cells).
Effects on the microbiome: Vitamin D influences gut microbiota composition, which is linked to CRC development by maintaining intestinal barrier function and immune homeostasis.
In summary, vitamin D acts as an active biological regulator through multiple cellular and immunological pathways, contributing to colorectal cancer prevention.
KH: What is the mechanism of how vitamin D may be beneficial as an adjunctive treatment of colon cancer?
MF & JTV: The active form of vitamin D supports CRC therapy through:
Antiproliferative effects by activating cell cycle inhibitors (p21, p27) that block tumor cell division.
Induction of apoptosis via activation of BAX/BAK pathways.
Inhibition of Wnt/β-catenin signaling, crucial in tumor development, and enhancement of E-cadherin and DKK-1 expression.
Immunomodulation and reduction of inflammation, including suppression of IL-6 and IL-8.
Antiangiogenic effects by decreasing HIF-1α and VEGF levels, inhibiting new blood vessel formation.
Potential improvement of chemotherapy response and reduction of recurrence risk, particularly with optimal serum vitamin D and micronutrient levels (e.g., magnesium).
Thus, vitamin D has complex cellular and immune effects that make it a promising adjuvant in personalized combined CRC treatment.
KH: What role does vitamin D adequacy play in the prevention of recurrence of colorectal cancer?
MF & JTV: Increasing evidence suggests adequate vitamin D levels are important not only in preventing CRC onset but also in reducing recurrence and progression. Calcitriol’s immunomodulatory, anti-inflammatory, cell cycle inhibitory, and pro-apoptotic effects may suppress residual tumor cells and prolong cancer-free survival.
Several clinical studies support this:
Although not all studies showed significant differences, overall data suggest vitamin D supplementation—especially achieving optimal serum levels—may reduce recurrence risk and improve survival, influenced by individual factors like BMI, magnesium intake, and baseline vitamin D status.
KH: What is a “preventive” blood level of vitamin D3?
MF & JTV: The preventive blood level refers to the optimal serum 25-hydroxyvitamin D concentration associated with reduced risk of CRC development and recurrence. Current literature generally accepts a minimum level of 30 ng/ml (75 nmol/L), above which protective effects increase.
Some studies suggest levels of 36–40 ng/ml (90–100 nmol/L) may offer even stronger protection. Levels below 30 ng/ml indicate insufficiency or deficiency, associated with higher cancer and chronic disease risk.
It is important to avoid excessively high levels (>100 ng/ml or 250 nmol/L), which pose health risks such as hypercalcemia.
In summary:
Minimum recommended: ≥ 30 ng/ml (75 nmol/L)
Optimal/preventive range: 36–40 ng/ml (90–100 nmol/L)
Potentially harmful level: > 100 ng/ml (250 nmol/L)
Individual needs and health status should guide supplementation, with medical supervision and regular monitoring.
KH: There is debate about the optimal serum level of vitamin D for cancer prevention, treatment and recurrence prevention. You leave a wide gap from ”Optimal” 36-40 ng/ml and ”Potentially harmful” > 100 ng/ml of 40-100 ng/ml? As a health practitioner who has done 1000s of vitamin D levels on patients I have never seen side effects under 100 ng/ml (unless they have parathyroid or kidney disease) and I see people taking 5000 IU routinely of vitamin D3 getting into the 30-50 ng/ml range. Personally for general health reasons and as someone who has had colon cancer I try and keep my vitamin D levels between 50-75 ng/ml. That takes about 10,000 IU per day 5-7 days per week. A 2000 IU/d dose for an adult seems to be low in my clinical experience to get levels even to 30 ng/ml? To me toxic side effects between 30-100 ng/ml are not an issue. What needs to be done is doses studied between 5000-10,000 IU per day to a get level between 50-100 ng/ml to see if there really is clinical benefit in colon cancer prevention, treatment and cancer recurrence.
1. Vitamin D Page 73 https://imahealth.org/wp-content/uploads/2023/06/Cancer-Care-FLCCC-Dr-Paul-Marik-v2.pdf
2. Vitamin D: Evidence-Based Health Benefits and Recommendations for Population Guidelines
You may have already addressed this in your answers above but do you have any additional comments on higher doses of vitamin D for prevention, adjunctive cancer treatment and prevention of cancer recurrence?
MF & JTV: Thank you for the thoughtful comments and clinical insights. We agree that the currently accepted optimal serum levels of vitamin D are indeed debated, particularly in oncology. While most population guidelines (including those from WHO and national authorities) define 30–50 ng/mL as a safe and physiologically sufficient range, some clinical observations — especially in cancer patients or those at high risk — suggest that higher levels (e.g., 50–75 ng/mL) might be beneficial.
However, it is important to note that vitamin D is a fat-soluble vitamin that accumulates in the body over time. Therefore, from a public health and safety standpoint, most national and international recommendations define 4000 IU/day as the tolerable upper intake level for healthy adults. Exceeding this level chronically may increase the risk of adverse events (e.g., nephrocalcinosis or hypercalcemia), especially in individuals with comorbidities or genetic susceptibilities.
In the SUNSHINE clinical trial — one of the most relevant interventional studies in metastatic colorectal cancer — patients received a bolus dose of 8000 IU/day only for the first 2 weeks, followed by 4000 IU/day as maintenance, confirming that even in oncology settings, long-term very high doses are typically avoided. PubMed link: https://pubmed.ncbi.nlm.nih.gov/30964527/
We fully acknowledge your clinical experience and agree that doses between 5000–10,000 IU/day may be necessary in certain cases (e.g., high BMI, limited sunlight exposure) to achieve higher serum levels. However, the long-term safety of sustained serum levels above 75–100 ng/mL still requires rigorous, randomized controlled trials, particularly in oncology.
Please note that we are not clinical oncologists, and in our article we approached the topic of vitamin D supplementation from a public health and preventive medicine perspective, not as a cancer treatment protocol. The SUNSHINE trial itself used only a short-term loading dose of 8000 IU/day followed by a maintenance dose of 4000 IU/day, which aligns with the globally recognized safe upper limit.
KH: What is a good blood level of vitamin D to achieve while someone is being treated for colon cancer?
MF & JTV: For CRC patients undergoing treatment, maintaining an optimal 25(OH)D level between 30–50 ng/ml (75–125 nmol/L) is advised. This range is associated with improved survival, reduced recurrence risk, and favorable effects on immune function and inflammation.
Evidence includes:
Epidemiological data linking serum 25(OH)D above 30 ng/ml to better prognosis and lower recurrence.
Hormonal effects of vitamin D that support anti-cancer mechanisms and enhance treatment efficacy.
Clinical practice recommends individualized supplementation with regular blood level monitoring, considering factors such as body weight, ethnicity, and ongoing therapies.
Avoiding toxic levels (>100 ng/ml) is crucial to prevent hypercalcemia.
Monitoring and maintaining appropriate vitamin D status is part of comprehensive cancer care to improve quality of life and outcomes.
KH: Can you tell us about your study and the basic results?
MF & JTV: Our study, titled “Vitamin D and Colorectal Cancer Prevention: Immunological Mechanisms, Inflammatory Pathways, and Nutritional Implications,” aimed to provide a comprehensive overview of vitamin D’s role in CRC prevention, focusing on immunological mechanisms, inflammatory pathways, and nutritional aspects.
We performed a literature review analyzing vitamin D’s various effects on CRC risk reduction. Key highlights include:
The active form, 1,25-dihydroxyvitamin D3, regulates tumor cell proliferation, promotes differentiation, and induces apoptosis, thereby inhibiting tumor growth.
Vitamin D modulates inflammatory signaling pathways (e.g., NF-κB, IL-6, TNF-α) critical in CRC pathogenesis.
Maintaining adequate vitamin D levels through sunlight exposure, diet, and supplementation is important for CRC prevention.
Epidemiological and clinical data collectively suggest that optimal 25(OH)D levels can reduce CRC incidence and improve survival.
We emphasize regular monitoring of vitamin D status, especially in high-risk populations.
Overall, our study supports that vitamin D plays a key role beyond bone health, acting through immune and inflammatory regulation to contribute to primary CRC prevention.
KH: Is there an advantage of vitamin D levels attained by being in the sun versus by vitamin D taken by mouth? Said differently, is there something from sun exposure that may additionally be beneficial for the prevention or treatment of colon cancer?
MF & JTV: Vitamin D levels can be raised both through skin synthesis triggered by sunlight exposure (UV-B radiation) and by oral vitamin D supplementation. However, vitamin D production via sunlight may have certain advantages. The synthesis of vitamin D3 in the skin is regulated by natural feedback mechanisms that limit excessive vitamin D formation, thereby reducing the risk of vitamin D toxicity. This regulation aligns with kidney-based control processes and represents the skin’s natural protective mechanism.
Moreover, UV radiation itself exerts multiple beneficial biological effects that may contribute to colorectal cancer prevention and treatment. Some studies have shown that sun exposure has positive immunomodulatory effects and promotes anti-inflammatory processes, which play important roles in slowing cancer progression. Vitamin D additionally induces apoptosis in certain cancer cell lines, including colorectal cancer cells, making the maintenance of adequate vitamin D levels crucial.
At the same time, sun exposure must be kept within safe limits to avoid the risk of skin cancer caused by excessive UV radiation. Proper photoprotection and avoiding sunburn maximize the benefits of sunlight-driven vitamin D synthesis. When UV exposure is limited—due to season, latitude, or other factors—oral vitamin D supplementation remains an effective and safe alternative.
In summary, vitamin D derived from sun exposure is advantageous not only due to its natural regulatory mechanisms but also because of the additional immune- and inflammation-modulating effects of UV radiation, which may contribute to colorectal cancer prevention and treatment. Achieving optimal effects requires both safe sun exposure practices and medically supervised vitamin D supplementation.
KH: How important is vitamin D as a single nutrient/hormone in the prevention, treatment, and prevention of recurrence of colon cancer?
MF & JTV: Vitamin D plays a significant role as a single nutrient and hormone in the prevention, treatment, and prevention of recurrence of colorectal cancer. Numerous epidemiological and clinical studies have demonstrated that maintaining adequate serum 25(OH)D levels—generally above 30 ng/mL (75 nmol/L)—is associated with a reduced risk of colorectal cancer and improved survival outcomes in patients.
Mechanistically, the active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D3), exerts multiple cellular effects that directly influence tumor progression. It promotes apoptosis of cancer cells, inhibits proliferation, reduces inflammation, and supports the effective functioning of the immune system. These actions are key not only in preventing tumor development but also in treating existing tumors and decreasing the risk of disease recurrence.
However, it is important to note that colorectal cancer is a complex disease influenced by numerous genetic, environmental, and lifestyle factors. Therefore, vitamin D should not be regarded as a standalone “miracle cure” but rather as part of a comprehensive preventive and therapeutic strategy that includes appropriate lifestyle, nutrition, and medical treatment.
In summary, vitamin D is a key nutrient and hormone in colorectal cancer prevention, treatment, and recurrence prevention, but its effectiveness is best realized within a multidisciplinary approach.
KH: Do you have any further comments on this interesting topic?
MF & JTV: Raising serum 25-hydroxyvitamin D levels above 30 ng/mL (75 nmol/L) can significantly contribute—based on many epidemiological and clinical studies—to reducing the risk of chronic diseases, including colorectal cancer. Higher vitamin D levels have also been associated with decreased mortality from conditions such as cardiovascular disease, stroke, diabetes, and respiratory infections.
Currently, vitamin D supplementation is the most effective and controllable method to achieve and maintain the desired 25(OH)D concentration, especially when sunlight-driven synthesis is limited. The optimal minimal daily dose for healthy adults with normal body weight is approximately 2000 IU (50 µg), which allows reaching serum levels of 30–40 ng/mL with minimal safety risks. Supplementation can be administered daily, weekly (e.g., 15,000 IU), or monthly (e.g., 60,000 IU), with weekly or monthly dosing often improving patient compliance.
Loading doses (“bolus”) given in the first one or two weeks can rapidly raise vitamin D levels, while lower doses maintain a stable concentration over time. This approach enables personalized supplementation, considering the patient’s baseline vitamin D status, lifestyle, and risk factors.
In Hungary, according to the updated 2022 “Hungarian Consensus Recommendation on the Role of Vitamin D in Disease Prevention and Treatment,” recommended vitamin D intake varies by age group. The goal is to maintain serum levels around or above 30 ng/mL, which may contribute long-term to colorectal cancer prevention, treatment, and reduction of recurrence risk.
Additionally, some recent publications highlight vitamin D3 supplementation’s potential benefits in anti-aging and general health maintenance: https://www.independent.co.uk/news/science/vitamin-d3-daily-anti-ageing-b2757496.html
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