B Vitamins and Cancer Risk: Riboflavin and Pyridoxine Show Promise, Folate and Cobalamin Remain Uncertain

B vitamins sit at the heart of one of the most contested questions in nutritional oncology: whether the very molecules that keep our DNA healthy can also influence our risk of developing cancer. A new structured narrative review published in Pathology and Oncology Research by Alexander Bertuccioli of the University of Urbino Carlo Bo, Chiara Maria Palazzi of the Microbiota International Clinical Society, and colleagues takes on this debate head-on, synthesizing evidence on four B vitamins—riboflavin (B2), pyridoxine (B6), cobalamin (B12), and folate (B9)—and their associations with the risk of selected cancers. The verdict is nuanced: two vitamins show potentially protective signals, particularly for colorectal cancer, while the other two remain stubbornly inconsistent and context-dependent.

The biological rationale for why B vitamins might matter in cancer is compelling. These water-soluble compounds function as coenzymes in one-carbon metabolism, the biochemical network that supplies methyl groups for DNA methylation and nucleotides for DNA synthesis and repair. Folate is converted to S-adenosylmethionine, the universal methyl group donor for DNA methylation, while vitamin B12 acts as a cofactor in that reaction and vitamin B6 supports several key enzymes in methyl group metabolism. A deficiency in these nutrients could, in theory, disrupt DNA integrity, impair repair mechanisms, and increase genetic mutations. Yet the same pathways raise a darker possibility: in cells with pre-existing neoplastic lesions, abundant folate might also fuel the proliferation of damaged tissue, a concern that has shadowed folic acid supplementation trials for decades.

The review team conducted a structured literature search in PubMed up to 2 September 2025, prioritizing meta-analyses—including dose-response meta-analyses—of observational studies, and incorporating randomized controlled trials of B-vitamin supplementation when clinically relevant. The initial search yielded 512 records; after screening, 120 articles were retained for full-text assessment and 45 studies made it into the final narrative synthesis. Although the work was not designed as a systematic review, the selection process followed a structured and transparent approach inspired by PRISMA recommendations, with three reviewers resolving disagreements through discussion. The team also appraised methodological quality narratively, focusing on exposure assessment, confounding, selection bias, and outcome assessment.

The clearest signal emerged for vitamin B6. In a meta-analysis of 28 observational studies, Lai and colleagues reported an inverse association between dietary pyridoxine intake and colorectal cancer risk (OR 0.80; 95% CI 0.68–0.94), while circulating pyridoxal 5′-phosphate—the active form of the vitamin—showed an even stronger protective association (OR 0.54; 95% CI 0.35–0.84). Favorable associations were particularly evident among women and for colon cancer specifically. The review’s summary table reports a relative risk of 0.56 (95% CI 0.46–0.67, p < 0.001) for the highest versus lowest dietary intake categories, with biomarker-based analyses suggesting risk reductions of 30 to 50 percent. In a large field synopsis of 121 observational studies, Mocellin and colleagues found that higher dietary B6 intake was associated with reduced risk of gastrointestinal cancers overall (RR 0.68; 95% CI 0.61–0.75), although site-specific findings for gastric cancer were less consistent.

Vitamin B6 also stood out for pancreatic cancer, one of the deadliest malignancies. Wei and Mao observed strong inverse associations, with relative risks of 0.63 (95% CI 0.48–0.79) for dietary intake and 0.65 (95% CI 0.52–0.79) for circulating pyridoxal 5′-phosphate. Their dose-response analysis indicated a 9 percent risk reduction per 10 nmol/L increment in circulating levels. Beyond the digestive tract, a dose-response meta-analysis by Qiang and colleagues reported that higher dietary intake of vitamin B6 and folate was associated with reduced risk of esophageal cancer, with relative risks of 0.57 (95% CI 0.47–0.69) for B6 and odds ratios of 0.62 (95% CI 0.56–0.68) for folate.

Riboflavin showed a more modest but still favorable pattern. An observational meta-analysis by Liu and colleagues found a protective association between vitamin B2 intake and colorectal cancer risk (OR 0.83; 95% CI 0.75–0.91). A Korean case-control study by Lu and colleagues involving 377 individuals with gastric cancer and 756 healthy controls suggested that regular riboflavin intake offers protection against gastric cancer, particularly in carriers of specific genetic variants of the MTRR gene involved in cobalamin metabolism. However, the picture is not uniformly rosy: a recent retrospective case-control study exploring blood riboflavin levels and colorectal cancer onset reported an increased risk proportional to circulating concentration, a finding that underscores how the source, dose, and timing of exposure may critically modify any apparent association.

Folate delivered the most context-dependent results. Moazzen and colleagues reported that randomized controlled trials of folic acid supplementation showed no significant effect on colorectal cancer risk (RR 1.07; 95% CI 0.86–1.43), whereas prospective cohort studies of dietary folate intake indicated a significant risk reduction (RR 0.71; 95% CI 0.59–0.86). This divergence between observational and interventional evidence suggests that dose, timing of exposure, baseline folate status, and background fortification policies may critically influence observed associations. Differences between naturally occurring folates and synthetic folic acid may also partly explain the lack of concordance. For breast cancer, a dose-response meta-analysis of prospective studies by Zhang and colleagues found no overall association (RR 0.97; 95% CI 0.90–1.05), but a J-shaped relationship emerged, with the lowest risk between 200 and 320 μg/day and an increased risk above 400 μg/day. For ovarian cancer, Wang and colleagues found no significant association with either dietary or total folate intake. Regarding melanoma, one meta-analysis of randomized controlled trials suggested a reduced risk with folic acid supplementation (RR 0.47; 95% CI 0.23–0.94), but larger pooled analyses involving more than 50,000 participants did not confirm this finding.

Vitamin B12 proved the most inconsistent of the four. A dose-response meta-analysis by Sun and colleagues indicated a modest inverse association with colorectal adenoma and cancer risk (RR 0.963 per +4.5 μg/day), with stronger effects for dietary intake compared with total intake. Yet for esophageal adenocarcinoma, the same dose-response meta-analyses revealed a positive association, with each additional 1 μg/day of cobalamin intake associated with a 2 percent increase in risk (OR 1.30; 95% CI 1.05–1.62). The review authors caution that this finding should not be overlooked, as it suggests cobalamin may have site-specific and context-dependent associations with cancer risk rather than uniformly neutral or protective effects. Possible effect modifiers include obesity, gastroesophageal reflux disease, alcohol consumption, and overall dietary patterns, alongside residual confounding inherent to observational research. For pancreatic cancer, no significant associations were identified for vitamin B12 (RR 0.99; 95% CI 0.59–1.38).

The review also contextualizes these findings within a broader landscape of B-vitamin oncology research. Long-term high-dose supplementation with vitamins B6 and B12 has been associated with increased lung cancer risk in specific subgroups such as male smokers, according to the VITAL cohort study by Brasky and colleagues. Randomized trials of folic acid supplementation have generally shown no significant protective effect on cancer incidence and, in some cases, have raised concerns about potential increases in cancer risk or progression, particularly in populations with pre-existing neoplastic lesions or high baseline exposure. Emerging evidence from Mendelian randomization studies provides additional support for a potential protective role of genetically predicted vitamin B6 across multiple cancer sites, though findings remain limited in number. Meanwhile, high-dose pyridoxine supplementation has been associated with neurotoxicity, particularly sensory neuropathy, a risk that becomes clinically relevant when supplementation exceeds physiological requirements or is used long term.

The authors conclude that the current body of evidence does not support the use of high-dose B-vitamin supplementation for primary cancer prevention in the general population. Rather, the findings are consistent with the importance of achieving adequate B-vitamin intake through balanced dietary patterns. The review acknowledges several limitations: the observational nature of most underlying evidence, susceptibility to residual confounding and dietary misclassification through food frequency questionnaires, considerable variability in baseline dietary patterns and fortification policies across geographic regions, and the frequent use of pharmacological doses in randomized trials that may not reflect habitual dietary intake. Future research should conduct well-designed prospective cohort studies with repeated dietary and biomarker assessments, integrate genetic and epigenetic markers to clarify mechanisms, and target high-risk subgroups such as individuals with folate deficiency, high alcohol consumption, pre-existing preneoplastic lesions, or genetic variants affecting one-carbon metabolism. Until then, the message remains clear: B vitamins are essential, but more is not necessarily better when it comes to cancer prevention.

Subject of Research: B vitamins intake and cancer risk: a structured narrative review of evidence on riboflavin, pyridoxine, cobalamin and folate

Article Title: B vitamins intake and cancer risk: a structured narrative review of evidence on riboflavin, pyridoxine, cobalamin and folate

Article References: Bertuccioli, A., Palazzi, C. M., Massaro, I. A., Cazzaniga, M., Cavecchia, I., Matera, M. R., Biagioli, V., Imperatori, L., Di Pierro, F., & Belli, A. (2026). B vitamins intake and cancer risk: a structured narrative review of evidence on riboflavin, pyridoxine, cobalamin and folate. Pathology & Oncology Research, 32, Article 1612380. https://doi.org/10.3389/pore.2026.1612380

Image Credits: AI Generated

DOI: 10.3389/pore.2026.1612380

Keywords: vitamins, intake, cancer, risk, structured, narrative, review, evidence, riboflavin, pyridoxine, cobalamin, folate