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

Table 1 Context-dependent and bidirectional immunomodulatory effects of vitamins in cancer

Vitamin	Immune compartment	Potential anti-tumor effect	Potential tolerogenic/pro-tumor or context-dependent effect	Ref.
Vitamin A/retinoids	Macrophages	Promote macrophage activation and tumor-cell clearance	Retinoid signaling can also support tissue tolerance depending on context	[82,83]
	DCs	Promote DC differentiation and antigen presentation	RA signaling can promote tolerogenic DC phenotypes in some tissues	[24,84]
	T cells	Enhance LTαβ signaling and tumor-cell apoptosis	RA can influence T-cell differentiation toward regulatory phenotypes	[25,28]
Vitamin B5	Macrophages	Support phagocytosis and antigen presentation	Cancer-specific mechanistic evidence remains limited	[44,85]
Vitamin B2/B6/B9	NK cells	Support NK-cell cytotoxic function under adequate nutritional status	Immunological outcomes strongly depend on metabolic and cytokine context; cancer-specific data are sparse	[56,86]
Vitamin C	NK cells/T cells	Enhance NK-cell proliferation and CD8+ T-cell cytotoxicity in pre-clinical models	Antioxidant effects may be context-dependent and could theoretically blunt ROS-dependent therapies	[7,14]
Vitamin D	Macrophages	Enhance phagocytosis in selected pre-clinical contexts	Can promote tolerogenic macrophage/DC programs and suppress T-cell activation	[23,52]
Vitamin E	DCs	Enhance DC cross-presentation in pre-clinical tumor models	Antioxidant activity may interfere with ROS-dependent anti-tumor mechanisms in some contexts	[9,87]
Vitamin K	T cells/macrophages	Emerging pre-clinical evidence for tumor-cell and macrophage-related effects	Potential T-cell suppression and immunoregulatory effects; robust clinical cancer immunology evidence remains limited	[88,89]

DCs: Dendritic cells; LTαβ: Lymphotoxin αβ; RA: Retinoic acid; NK: Natural killer; ROS: Reactive oxygen species.

Table 2 Clinical and preclinical use scenarios of vitamin-based interventions in cancer immunotherapy

Strategy	Use setting	Implementation	Immune/clinical readout	Status/Ref.	Evidence level (tier)
ATRA + pembrolizumab	Metastatic melanoma; phase I/II and 5-year update	ATRA was paired with anti-PD-1 to target myeloid suppression	MDSC differentiation, restored T-cell activity, and partial durable clinical responses	Clinical signal; sequencing matters[10,19]	Tier 3
Vitamin D3 repletion + ICI therapy	Advanced melanoma and real-world advanced-cancer ICI cohorts	Serum 25(OH)D was monitored and corrected with cholecalciferol	Associations with higher ORR/PFS/OS and reduced thyroid immune-related adverse events; causal efficacy not proven	Observational correlative findings; independent prospective interventional validation required[11,20]	Tier 2
Vitamin D intake before ICI therapy	Melanoma anti-PD-1/anti-CTLA-4 cohorts	Pretreatment vitamin D intake recorded at ICI initiation	Lower odds of immune checkpoint inhibitor-induced colitis	Toxicity-reduction hypothesis from retrospective data[21]	Tier 2
NAM-expanded NK cells	Relapsed/refractory non-Hodgkin lymphoma NK-cell platform	Nicotinamide used ex vivo during NK-cell manufacturing	Improved fitness, homing, persistence and cytotoxicity; clinical remissions	Clinical cell-therapy reagent, not nutritional supplementation[12]	Tier 3
Vitamin E/SCARB1-SHP1	ICI-treated patient records plus mouse tumor models	Vitamin E entered DCs via SCARB1 and inhibited SHP1	Enhanced DC cross-presentation, DC-EVs and T-cell priming	Pre-clinical mechanistic finding plus retrospective correlative data[9]	Tier 1/Tier 2
Pharmacological vitamin C + anti-PD-1	NSCLC in vitro and syngeneic in vivo models	High-dose ascorbic acid combined with anti-PD-1	Macrophage IL-12/phagocytosis and CD8+ T-cell cytotoxicity increased	Purely pre-clinical adjuvant concept; IV exposure likely required[14]	Tier 1
Vitamin C vitcylation	Tumor-cell and immune-activation models	Vitamin C induced STAT1 K298 vitcylation	IFN-γ signaling and MHC/HLA-I antigen presentation increased	Mechanistic biomarker for ascorbate combinations[15]	Tier 1
RA biosynthesis/RAR modulation	DC vaccine, RA-high tumors and senescence models	ALDH1A2/ALDH1A3 blockade or RAR activation modulated local RA signaling	Restored DC/T-cell priming and enhanced NK-mediated clearance	Preclinical pathway modulation[13,16,17]	Tier 1

For human-derived entries: All-trans retinoic acid + pembrolizumab: Phase I/II single-arm open-label trial (n = 24 metastatic melanoma); vitamin D3 repletion + immune checkpoint inhibitor: Mixed retrospective/prospective observational cohorts without randomization; nicotinamide-expanded natural killer cells: Single-arm phase I-II cell-therapy trial in relapsed/refractory non-Hodgkin lymphoma. No placebo-controlled large-scale phase-III trials are available for these vitamin-related immunotherapy combinations. Definitions of evidence-level tiers adopted in this review. Tier 1: Pre-clinical mechanistic evidence derived from in vitro cell experiments or syngeneic animal tumor models, without validation in human intervention studies. Tier 2: Human observational or retrospective correlative evidence (cohort studies, electronic-health-record analyses); these associations cannot prove causality and are susceptible to confounding factors. Tier 3: Preliminary human interventional clinical signals obtained from phase I/II trials or prospective interventional cohorts; robust large-scale phase-III randomized controlled trials confirming generalizable clinical efficacy are still lacking. Note that highernumbered tiers do not equate to established routine clinical applicability. ATRA: All-trans retinoic acid; PD-1: Programmed cell death 1; MDSC: Myeloid-derived suppressor cell; ICI: Immune checkpoint inhibitor; 25(OH)D: 25-hydroxyvitamin D; ORR: Objective response rate; PFS: Progression-free survival; OS: Overall survival; CTLA-4: Cytotoxic T-lymphocyte antigen-4; NAM: Nicotinamide; NK: Natural killer; DCs: Dendritic cells; EVs: Extracellular vesicles; SCARB1: Scavenger receptor class B member 1; SHP1: Src-homology-2-domain-containing protein-tyrosine phosphatase-1; NSCLC: Non-small cell lung cancer; IL-12: Interleukin-12; IV: Intravenous; STAT1: Signal transducer and activator of transcription 1; IFN-γ: Interferon gamma; MHC: Major histocompatibility complex; HLA: Human leukocyte antigen; RA: Retinoic acid; RAR: Retinoic acid receptor; ALDH: Aldehyde dehydrogenase.

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.