Vitamin-mediated cancer immune reprogramming: Context-dependent mechanisms and translational perspectives

Table 3 Translational considerations and unresolved challenges for vitamin-based immunomodulation

Vitamin	Intervention type	Pharmacokinetics/pharmacodynamics considerations	Deficiency correction vs pharmacological modulation	Key translational limitation
Vitamin A	Retinoid/ATRA-based pharmacological intervention	Tissue-specific retinoid metabolism strongly determines effective biological exposure[3,90]	Deficiency correction (nutritional repletion) vs pharmacological high-dose retinoid pathway modulation	Pharmacological ATRA may induce tolerogenic immune programs and carry known toxicities (mucocutaneous toxicity, teratogenic risk). Optimal therapeutic windows remain poorly defined in oncology settings
Vitamin B	Nutritional supplementation/ex vivo intervention (NAM-based cell manufacturing)	Immune effects tightly coupled to intracellular NAD-dependent metabolic status[91]	Nutritional supplementation for physiological support vs ex-vivo metabolic conditioning for cell products	Robust clinical evidence supporting systemic B-vitamin adjuvant effects during ICI therapy remains absent
Vitamin C	Nutritional supplementation (oral)/pharmacological intervention (high-dose IV ascorbate)	Exposure is strictly route-dependent; pharmacological tumor-relevant concentrations can only be achieved via intravenous infusion[92]	Physiological oral repletion for antioxidant homeostasis vs high-dose intravenous pharmacological intervention generating pro-oxidant tumor stress	Optimal dose, timing and combination regimens for cancer immunotherapy are unresolved; high-dose IV ascorbate carries renal safety risks[72]
Vitamin D	Nutritional supplementation for deficiency correction	Serum 25(OH)D reflects status but not necessarily tissue exposure[52]	Primarily nutritional supplementation for deficiency correction; clinical evidence for pharmacological-dose modulation remains limited	Target serum 25(OH)D cut-offs for ICI benefit are not validated; serum 25(OH)D cannot serve as a standalone predictive biomarker for immunotherapy response
Vitamin E	Nutritional supplementation (oral)	Lipid-soluble tissue distribution and antioxidant properties[93]	Almost exclusively limited to nutritional-status correction	Potential risk of interfering with ROS-dependent anti-tumor therapeutic mechanisms; lack of human interventional trials in ICI-treated patients
Vitamin K	Nutritional supplementation/potential pharmacological intervention for pathway modulation	Tissue distribution and biological activity differ across isoforms and are not fully characterized[94]	Predominantly nutritional repletion; pharmacological modulation remains pre-clinical	Limited cancer immunotherapy human data; critical drug-drug interaction risk with vitamin-K-targeted anticoagulant agents[61]

ATRA: Antigen-presenting cell; NAM: Nicotinamide; ICI: Immune checkpoint inhibitor; 25(OH)D: 25-hydroxyvitamin D; ROS: Reactive oxygen species.