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

Abstract

Vitamins are increasingly recognized not as passive dietary cofactors or interchangeable antioxidants but as context-sensitive immunometabolic regulators that can reshape antigen presentation, natural killer (NK)-cell fitness, T-cell exhaustion, tumor-cell immunogenicity, and potential responsiveness to immune checkpoint inhibitor therapy. This review synthesizes mechanistic and translational evidence linking vitamins A, B, C, D, E, and K to anti-tumor immunity. We advance three organizing principles. First, vitamin biology is profoundly context-dependent: The same retinoid, calcitriol, ascorbate, or antioxidant pathway can enforce immune tolerance or restore cytotoxic immunity depending on dose, pharmacokinetics, tissue compartment, tumor genotype, cellular source, and treatment sequence. Second, vitamin actions extend beyond redox buffering to epigenetic and post-translational control, exemplified by vitamin C-driven TET-dependent remodeling and signal transducer and activator of transcription 1 lysine vitcylation, which amplifies interferon signaling and major histocompatibility complex-I antigen presentation in pre-clinical models. Third, vitamins hold promise as biomarker-guided adjuvants rather than empiric supplements; however, most candidate biomarkers, apart from serum 25-hydroxyvitamin D, tumor glucose transporter 1, aldehyde dehydrogenase, retinoic acid (RA) receptor activity, dendritic cell (DC) Src-homology-2-domain-containing protein-tyrosine phosphatase-1 (SHP1) protein tyrosine phosphatase signaling, or NK-cell metabolic fitness, lack prospective clinical validation in cancer patients. We integrate available clinical observations alongside pre-clinical mechanistic findings on vitamin D status monitoring during anti-programmed cell death 1 (PD-1) therapy, nicotinamide-expanded NK-cell adoptive transfer, retinoic-acid-pathway modulation for DC-based vaccines, pre-clinically described vitamin E-scavenger receptor class B member 1-SHP1 signaling, and pre-clinical pharmacological ascorbate combined with anti-PD-1 therapy. We therefore propose a precision vitamin-mediated immunotherapy framework that prioritizes deficiency correction, drug-like exposure, immune-contexture mapping, therapeutic sequencing, and mandatory prospective randomized validation. Notably, most biomarker-driven intervention strategies outlined in this review remain exploratory and are not ready for routine clinical application.

Key Words: Vitamins; Immunometabolism; Tumor microenvironment; Immune checkpoint inhibitor therapy; Dendritic cells; Natural killer cells; Precision vitamin immunotherapy

Core Tip: Vitamins are context-dependent immunometabolic regulators reshaping anti-tumor immunity and immune checkpoint inhibitor response beyond simple antioxidant function. This review summarizes mechanistic and translational evidence of vitamins A/B/C/D/E/K in tumor immunity, putting forward three core principles covering dose-dependent immune effects, epigenetic regulatory mechanisms, and biomarker-guided adjuvant application. We propose a precision vitamin-targeted immunotherapy framework combining deficiency correction, standardized supplementation and matched immune background to optimize tumor immunotherapy efficacy.

INTRODUCTION

Cancer immunotherapy has transformed the treatment of multiple malignancies, but therapeutic responses remain highly heterogeneous. Increasing evidence indicates that the metabolic state of the tumor microenvironment (TME) critically shapes antigen presentation, myeloid-cell polarization, lymphocyte function, and tumor immunogenicity. Vitamins, traditionally regarded as essential micronutrients, are increasingly recognized as regulators of these processes through their effects on metabolism, redox homeostasis, transcription, and epigenetic regulation[1-4]. For example, vitamin C participates in TET-dependent DNA demethylation, while its oxidized form, dehydroascorbic acid (DHA), can enter cells through glucose transporters[4,5]. Importantly, vitamin-mediated effects are not uniformly beneficial and may vary with dose and metabolic context; vitamin C, for instance, can exert antioxidant or pro-oxidant effects depending on exposure[6-8].

Vitamins can regulate multiple components of anti-tumor immunity, including macrophages, dendritic cells (DCs), natural killer (NK) cells, and T and B lymphocytes[9-17] (Table 1). Their effects are highly context-dependent, shaped by dose, administration route, tissue compartment, tumor metabolism, immune state, and therapeutic sequence. Consequently, vitamins should not be viewed simply as universal “immune boosters”. Rather, their therapeutic potential depends on which vitamin-dependent pathway is engaged, in which cellular compartment, and under which treatment conditions. Vitamin-derived interventions may enhance anti-tumor immunity, remodel the TME, or improve cellular immunotherapy[9-21] (Figure 1), whereas indiscriminate supplementation may be ineffective or even detrimental in specific clinical contexts[22-25].

Figure 1 Vitamins can regulate anti-tumor immunity through both reductive/antioxidant and oxidative/pro-oxidant mechanisms. In reductive regulatory programs, vitamins enhance immune-cell functions that support tumor elimination, including macrophage phagocytosis and cytotoxicity, T-cell-mediated killing, B-cell activation, NK-cell oncolytic activity, and DC differentiation and maturation. In oxidative programs, pharmacological vitamin exposure, especially high-dose ascorbate in susceptible contexts, can increase ROS-dependent stress, damage tumor-cell proteins and organelles, and promote tumor-cell death. NK: Natural killer; DC: Dendritic cell; ROS: Reactive oxygen species.

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.

These observations support a shift from empirical supplementation toward biomarker-guided vitamin immunotherapy. Candidate biomarkers include serum 25-hydroxyvitamin D [25(OH)D] and exploratory markers related to tumor metabolic susceptibility, retinoid signaling, DC function, and NK-cell metabolic fitness[26-32]. However, most remain insufficiently validated for clinical decision-making, and prospective studies are needed to define appropriate patient selection, dose, exposure, treatment sequence, and clinical endpoints. In this review, we examine vitamins A, B, C, D, E, and K as context-dependent immunometabolic regulators of cancer therapy, integrating their effects across immune compartments and evaluating their mechanistic, translational, and clinical evidence. We further propose a biomarker-guided framework for precision vitamin intervention and highlight the experimental and clinical requirements for its translation (Figure 2).

Figure 2 Immunomodulatory effects of vitamins within the tumor microenvironment. Vitamins modulate multiple immune-cell compartments within the tumor microenvironment. All immunomodulatory outcomes depicted are predominantly supported by tier 1 pre-clinical evidence (in vitro and mouse tumor models), unless otherwise noted. Vitamins exert anti-tumor influences via two distinct routes: The reductive regulation route that boosts intrinsic anti-tumor immune-cell function, and the oxidative-damage route in which pharmacological-dose vitamin exposure triggers reactive oxygen species-dependent tumor-cell injury. All immunomodulatory outcomes depicted are predominantly supported by tier 1 pre-clinical evidence (in vitro cell experiments and mouse tumor models), unless otherwise specified. In the reductive-regulation route, dietary or supplemented vitamins enhance anti-tumor functions of macrophages, T cells, B cells, natural killer cells and dendritic cells, collectively driving tumor-cell elimination. In the oxidative-damage route, pharmacological vitamin exposure (especially high-dose ascorbate in susceptible tumor contexts) induces oxidative stress, causing structural damage to tumor-cell proteins and organelles and promoting tumor-cell death. Corresponding human interventional evidence for most of these mechanistic observations remains limited. Corresponding human interventional evidence for most of these mechanistic observations remains limited. IL-12: Interleukin-12; TNF: Tumor necrosis factor; DC: Dendritic cell; MHC: Major histocompatibility complex; TCR: T cell receptor; LTαβ: Lymphotoxin αβ; LTβR: Lymphotoxin β receptor; RA: Retinoic acid; ICAM-1: Intercellular adhesion molecule 1; LFA-1: Lymphocyte function-associated antigen-1; NK: Natural killer; GLUT1: Glucose transporter 1.

LITERATURE SEARCH AND SELECTION STRATEGY

Search databases and time window

A structured literature search was conducted to identify studies investigating the immunomodulatory functions of vitamins in the TME and their translational potential in cancer immunotherapy. Literature retrieval was performed using the Web of Science Core Collection, PubMed, EMBASE and ClinicalTrials.gov. The primary publication period covered January 1983 to September 2026. The final date of database searching was September 10, 2026. Earlier studies were retained when they provided important historical, mechanistic, or conceptual foundations. When multiple studies addressed similar questions, recent primary studies and clinically informative cohorts or trials were preferentially considered.

Search strategy and keywords

The search strategy consisted of three keyword groups covering vitamins, tumor immunity, and cancer immunotherapy. Vitamin-related terms included vitamin A, RA, all-trans RA (ATRA), vitamin B, nicotinamide (NAM), vitamin C, ascorbate, dehydroascorbic acid, 25(OH)D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], vitamin E, vitamin K, and retinoids. Immune-related terms included tumor microenvironment, immunometabolism, macrophage, tumor-associated macrophage, dendritic cell, natural killer cell, T-cell exhaustion, regulatory T cell, antigen presentation, and myeloid-derived suppressor cell. Immunotherapy-related terms included immune checkpoint inhibitor, anti-PD-1, anti-PD-L1, adoptive cell therapy, dendritic cell vaccine, and cancer immunotherapy. These terms were combined using Boolean operators (AND/OR) and adapted to the syntax of each database. Representative PubMed search string example: (“vitamin A” OR retinoic acid OR ATRA OR “vitamin B” OR nicotinamide OR “vitamin C” OR ascorbate OR “vitamin D” OR “vitamin E” OR “vitamin K” OR retinoid) AND (“tumor microenvironment” OR immunometabolism OR macrophage OR “dendritic cell” OR “natural killer cell” OR T-cell exhaustion) AND (“cancer immunotherapy” OR “immune checkpoint inhibitor” OR anti-PD-1 OR anti-PD-L1).

Study selection and evidence classification

Studies were considered eligible if they investigated vitamin-mediated immune mechanisms using in vitro cellular models, in vivo tumor models, or human immune cells, or if they provided clinical evidence from observational studies, prospective clinical trials, or registered clinical trials involving vitamin-based interventions in cancer immunotherapy. Relevant systematic and narrative reviews were also considered for mechanistic and conceptual context. Priority was given to peer-reviewed English-language publications. Non-English publications were only considered if complete, informative English abstracts were publicly available; preprints were not included unless subsequently published in peer-reviewed journals. For trial records retrieved from ClinicalTrials.gov, only registered trials with available posted study protocol or result summaries were retained; registry-only entries without public study details were excluded. Selected high-quality studies were included when detailed immune-related findings and complete English abstracts were available. Studies were excluded if they were limited to dietary or epidemiological associations without mechanistic immune evidence, single case reports, conference abstracts lacking sufficient experimental or clinical information, studies focusing exclusively on tumor-cell proliferation or apoptosis without immune-related endpoints, duplicate publications, or repeated analyses of identical datasets. Studies with major and unresolvable methodological or statistical limitations were also excluded.

Supplementary retrieval and scope of the review

Additional studies were identified by manually screening the reference lists of highly cited publications and by conducting targeted searches of key mechanistic pathways discussed in this review, including TET-dependent demethylation, signal transducer and activator of transcription 1 (STAT1) lysine vitcylation, DC scavenger receptor class B member 1 (SCARB1)-Src-homology-2-domain-containing protein-tyrosine phosphatase-1 (SHP1) signaling, and the aldehyde dehydrogenase (ALDH)-retinoid pathway.

Literature screening was independently performed by two authors. Titles and abstracts were first screened for preliminary eligibility; full-text articles were subsequently assessed against the predefined inclusion and exclusion criteria. Any disagreements regarding study eligibility were resolved through group discussion among all authors until consensus was reached. After deduplication, the initial database search yielded 1428 records. Following title-abstract screening, 264 full-text articles were assessed for eligibility. Ultimately, 102 references were included for qualitative narrative synthesis in this review.

This study is a narrative review rather than a formal systematic review. Therefore, no quantitative meta-analysis or formal risk-of-bias assessment was performed. The substantial heterogeneity in vitamin formulations and doses, administration routes, tumor types, treatment contexts, and immune endpoints precluded quantitative synthesis. Nevertheless, the search and screening procedures were systematically documented to improve transparency and reduce potential selective citation.

Evidence-tier classification

To stratify the strength of available evidence across preclinical and human studies, we adopted a three-tier classification framework: (1) Tier 1: Pre-clinical mechanistic evidence derived from in vitro cell experiments or syngeneic animal tumor models, without validation in human intervention studies; (2) 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; and (3) 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 higher-numbered tiers do not equate to established routine clinical applicability. This tier classification is also summarized in Table 2 for quick reference.

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.

Definitions of intervention categories

Three distinct intervention modalities are discriminated throughout this review: (1) Nutritional supplementation: Physiological-dose administration aiming to correct vitamin deficiency or maintain physiological nutrient status (oral dietary-level supplementation); (2) Pharmacological intervention: Supra-physiological, drug-like exposure to vitamins or vitamin derivatives intended to reprogram intracellular signaling pathways (e.g., high-dose intravenous ascorbate, pharmacological ATRA); and (3) Ex vivo intervention: Vitamin exposure applied to isolated immune cells during cell manufacturing, prior to patient adoptive transfer. Ex vivo conditioning results must not be extrapolated to in vivo oral nutritional supplementation.

CORE CONTEXT-DEPENDENT RULES FOR VITAMIN IMMUNOREGULATION

The immunomodulatory effects of vitamins are not static but are shaped by dose, treatment timing, tissue and cellular context, and tumor-intrinsic characteristics. These variables provide a unified framework for understanding the divergent effects of vitamins across different therapeutic settings.

Dose dependence and biphasic pharmacological effects

Many vitamin pathways exhibit dose-dependent biological effects. Physiological replacement primarily corrects deficiency and supports immune homeostasis, whereas pharmacological exposure can alter intracellular signaling, metabolism, and redox state. Such dose-dependent behavior also applies to vitamin D: Physiological vitamin D maintains immune homeostasis, whereas high-dose effects observed in preclinical models lack consistent human validation. For antioxidant vitamins, this distinction can be particularly important. Physiological antioxidant activity may support cellular redox homeostasis, whereas pharmacological ascorbate can generate hydrogen peroxidemediated oxidative stress in susceptible tumor contexts[33-37] (Figure 3). Thus, pharmacological intervention with high-dose ascorbate should not be equated mechanistically with routine nutritional supplementation for antioxidant purposes.

Figure 3 Biomarker-guided vitamin strategies for immune reprogramming in cancer immunotherapy. This schematic summarizes a hypothetical conceptual precision framework for integrating vitamin-derived interventions into cancer immunotherapy. It is not a ready-to-use clinical decision-making algorithm. Rather than treating vitamins as empirical supplements, the workflow links defined biomarkers to mechanistically matched immune-reprogramming strategies and measurable therapeutic outputs. Among biomarkers shown in the left panel: Only serum 25-hydroxyvitamin D represents a clinically available nutritional status marker. All other biomarkers [glucose transporter 1/dehydroascorbic acid transport, SVCT expression, signal transducer and activator of transcription 1 vitcylation, aldehyde dehydrogenase (ALDH)1A2/ALDH1A3-retinoic acid receptor signaling, scavenger receptor class B member 1-Src-homology-2-domain-containing protein-tyrosine phosphatase-1 (SHP1) signaling, natural killer (NK)-cell metabolic fitness] are exploratory tier 1 pre-clinical candidates without prospective human clinical validation. The central panel illustrates corresponding interventions: Vitamin D3 repletion during immune checkpoint blockade, pharmacological ascorbate to enhance tumor immunogenicity and anti-programmed cell death 1 responsiveness, vitamin E-mediated dendritic cell reinvigoration through SHP1 inhibition, retinoic-acid-pathway blockade or activation to remodel tolerance, all-trans retinoic acid-mediated differentiation of suppressive myeloid cells, and nicotinamide-based NK-cell manufacturing. Most of these intervention-biomarker pairings are derived from pre-clinical mechanistic studies. Only nicotinamide-based ex vivo NK-cell manufacturing has preliminary clinical supporting evidence. The right panel defines the immune and clinical outputs that should be prospectively measured in future investigations, including antigen presentation, dendritic-cell cross-presentation, macrophage phagocytosis and interleukin-12 signaling, NK-cell persistence and cytotoxicity, CD8⁺ T-cell infiltration and effector function, reversal of exhaustion, response durability, and immune-related toxicity. The central message is that vitamin-mediated immune reprogramming requires biomarker validation, exposure control, immune-compartment definition, and prospective randomized clinical trials before any real-world clinical adoption. Notably, this diagram serves solely as a hypothesis-generating conceptual framework; most candidate biomarkers and intervention matching strategies remain preclinically exploratory without prospective clinical validation, and cannot be directly applied as a decision-making tool for routine clinical practice. 25(OH)D: 25-hydroxyvitamin D; PD-1: Programmed cell death 1; ATRA: All-trans retinoic acid; MDSC: Myeloid-derived suppressor cell; RA: Retinoic acid; SHP1: Src-homology-2-domain-containing protein-tyrosine phosphatase-1; DC: Dendritic cell; IFN-γ: Interferon gamma; STAT1: Signal transducer and activator of transcription 1; MHC: Major histocompatibility complex; IL-12: Interleukin-12; TME: Tumor microenvironment; NK: Natural killer; IV: Intravenous; ICI: Immune checkpoint inhibitor.

Intervention timing and therapeutic sequence dependence

The relative timing of vitamin exposure and standard therapy may influence the net therapeutic effect. Concurrent antioxidant exposure may attenuate reactive oxygen species (ROS)-dependent treatment responses in some experimental settings, whereas selected pharmacological vitamin regimens may show benefit when deliberately sequenced with immunotherapy or cellular therapy. Notably, such sequencing-dependent outcomes also extend to vitamin C-TET-dependent DNA demethylation; the epigenetic reprogramming triggered by pharmacological ascorbate may prime tumor or immune compartments and synergize with subsequent immunotherapeutic interventions, yet this potentiation can be blunted if vitamin C is administered in an incompatible temporal order. These observations support, but do not yet establish, treatment-sequence stratification as a component of biomarker-guided intervention[2,7].

TME compartment dependence

Vitamin bioavailability, transporter expression, metabolic flux, and downstream effector outputs differ markedly across tumor compartments and immune-cell subsets. Hypoxia, nutrient deprivation, extracellular acidification, and aberrant redox states within the TME can alter vitamin metabolism and reshape immune-cell function. For example, vitamin C can regulate myeloid responses through hypoxia-inducible factor (HIF)-dependent signaling and redox remodeling, whereas vitamin A/retinoid and vitamin D signaling can influence myeloid and lymphoid differentiation, antigen presentation, and regulatory T-cell programs[19,38,39]. Vitamin E may additionally affect immune-cell function through its lipid-phase antioxidant activity, although its effects on antitumor immunity remain less clearly defined[9].

Tumor intrinsic genotype and background dependence

Oncogenic drivers, tumor metabolic states, transporter expression, and endogenous antioxidant capacity may influence sensitivity to vitamin-derived interventions. For example, glucose transporter 1 (GLUT1)-dependent DHA uptake has been proposed as one determinant of pharmacological ascorbate sensitivity, while ALDH-retinoid activity may shape responses to retinoid-pathway modulation[5,6,16,17]. These observations provide a rationale for biomarker stratification, but most proposed molecular markers remain exploratory.

CELL-SPECIFIC IMMUNOMODULATION OF CLASSIC VITAMINS (A, C, D, E)

Regulation of tumor-associated macrophage polarization and function by vitamins A, B5, C, and D

Vitamins can influence tumor-associated macrophage (TAM) polarization, phagocytic activity, cytokine production, and anti-tumor function, with the direction of the effect depending on dose and local TME context[23,40,41]. Vitamin C remodels TAM phenotypes predominantly through regulating HIF signaling cascades. Ascorbate serves as an essential cofactor for HIF hydroxylases, thereby restraining HIF-1α/HIF-2α activation in myeloid cells; myeloid-specific HIF ablation has been validated to suppress tumor progression in fibrosarcoma and breast cancer murine models[4]. In syngeneic non-small cell lung cancer mouse models, high-dose vitamin C combined with anti-programmed cell death 1 (PD-1) immunotherapy significantly increases intratumoral macrophage infiltration, promotes interleukin-12 (IL-12) secretion, and further enhances the cytotoxic activity of intratumoral CD8⁺ T cells[14].

Active 1,25(OH)₂D₃ facilitates M1-like macrophage polarization and enhances macrophage-mediated Burkitt lymphoma cell elimination in both in vitro cell cultures and murine models[42]. Low-dose vitamin A reinforces macrophage tumoricidal function by promoting the secretion of cytotoxic effector molecules[43]. Vitamin B5 is closely linked to coenzyme A-dependent metabolic processes, and emerging cancer-focused evidence also suggests a tumor-intrinsic role for B5. In breast cancer models, vitamin B5 availability has been reported to support MYC-associated oncogenic metabolism and tumor progression. These findings indicate that the biological effects of B5 in cancer are not necessarily immunostimulatory and may depend strongly on the cellular compartment and metabolic context[44]. Notably, all above phenotypic and mechanistic findings are exclusively validated in preclinical cell and animal models, without consistent verification in primary human TAMs isolated from clinical specimens. Note that some underlying mechanistic observations for vitamin-modulated macrophage function originate from infection-related experimental systems, and may not be fully recapitulated within the complex TME.

Retrospective cohort studies have suggested associations between vitamin status and immune-related outcomes, but these observations do not establish causal macrophage reprogramming. In multiple myeloma and other cancer settings, vitamin D pathway activity has been investigated as a modifier of immune function; however, tumor-tissue macrophage endpoints have rarely been prospectively measured. Historical multivitamin studies in bladder cancer likewise predate contemporary immunotherapy and should be interpreted as hypothesis-generating rather than mechanistic evidence. Beyond vitamin-mediated regulation of macrophages, certain vitamin-derived metabolites also exert critical functions in the development of other key immune cell subsets, as exemplified by RA. RA also participates in the developmental regulation of dendritic-cell subsets. Experimental studies in mice have demonstrated an important role for RA in the development of specific splenic dendritic-cell populations[45]. These findings provide a developmental basis for the broader context-dependent effects of retinoid signaling on dendritic-cell biology.

To date, no completed prospective randomized controlled trials have specifically explored whether vitamin A, B5, C, or D supplementation (monotherapy or combination regimens) can effectively remodel TAM polarization and improve immune checkpoint inhibitor (ICI) efficacy in solid tumor populations. Available vitamin D repletion trials only record general survival outcomes, without predefined myeloid immune endpoints to quantitatively evaluate TAM phenotypic transformation after intervention. Accordingly, tier 3 preliminary interventional clinical evidence supporting TAM-targeted vitamin adjuvant therapy is currently absent.

DC-mediated vitamin responses in cancer

As summarized in above, vitamins exert context-dependent effects on DC-driven anti-tumor immunity. DCs serve as central initiators of tumor-specific adaptive anti-tumor immunity by mediating antigen uptake, cross-presentation and naive T cell priming[46,47]. Multiple vitamins shape DC differentiation, maturation, cytokine secretion and intrinsic checkpoint signaling in preclinical systems. RA can support conventional dendritic-cell differentiation in defined physiological contexts, whereas sustained local retinoid signaling may also favor tolerogenic antigen presentation. In tumor models, inhibition of ALDH1A2/ALDH1A3-dependent RA synthesis can relieve local immune tolerance and improve DC vaccine activity[4,16,17].

Vitamin E crosses DC membranes via the transporter SCARB1 to suppress intracellular phosphatase SHP1; SHP1 inhibition relieves intrinsic negative regulation of antigen cross-presentation, elevates DC-derived Th1 cytokine release, and amplifies antigen-specific CD8⁺ T cell activation in mouse tumor models[9]. Importantly, the DC-specific SCARB1-SHP1 immune checkpoint pathway remains a purely preclinical finding. No clinical assay is available to quantify SHP1 activity in human DCs, and no prospective clinical study has confirmed that vitamin E supplementation can modulate this pathway in cancer patients. Vitamin C can promote inflammatory cytokine production and T-cell priming in experimental DC systems, whereas 1,25(OH)₂D₃ can promote tolerogenic differentiation of human monocyte-derived DCs under defined culture conditions[48,49]. These findings illustrate the bidirectional nature of vitamin-mediated DC regulation.

All molecular and cellular regulatory mechanisms described above are exclusively validated in vitro DC culture and syngeneic mouse tumor models. No prospective human intervention study has verified that oral vitamin E, vitamin C or retinoid modulators can stably reprogram DC function in cancer patients.

Limited observational evidence has linked vitamin exposure or status with outcomes during cancer immunotherapy. Retrospective electronic-health-record analyses have associated vitamin E supplementation with outcomes during immune checkpoint blockade, while melanoma cohorts have associated adequate baseline serum 25(OH)D with improved anti-PD-1 outcomes[11]. These associations remain vulnerable to confounding by nutritional status, health behavior, inflammation, and concurrent treatment.

No completed phase I/II prospective trials have systematically assessed how standardized vitamin E, vitamin C or retinoid intervention modulates human DC cross-presentation capacity in ICI-treated patients. Registered DC vaccine clinical trials rarely incorporate vitamin adjuvant supplementation as a fixed combinatorial arm, and no randomized controlled trials have validated clinical efficacy of vitamin-modified DC vaccine regimens for solid tumors. Tier 3 preliminary interventional clinical evidence supporting routine vitamin co-administration to boost DC-mediated anti-tumor immunity is lacking.

NK cell-mediated vitamin responses in cancer

NK cells mediate major histocompatibility complex (MHC)-unrestricted tumor surveillance. Experimental studies indicate that retinoid and vitamin C pathways can influence NK-cell abundance, maturation, and cytotoxic function, whereas NAM has shown a particularly clear translational role when used as an ex vivo metabolic conditioning agent during NK-cell manufacturing; this ex vivo benefit cannot be generalized to oral nutritional supplementation of NAM in patients[12,13].

Available human evidence linking vitamin deficiency to impaired NK-cell function remains limited and heterogeneous. More importantly, clinical cohorts have not established that long-term oral vitamin supplementation reliably increases tumor-infiltrating NK-cell function. Thus, systemic supplementation and ex vivo metabolic conditioning should not be treated as equivalent interventions.

Prospective ex vivo cell manufacturing trials confirm that NAM priming during NK cell expansion improves NK metabolic fitness, tumor homing, in vivo persistence, and cytotoxic activity. Adoptive transfer of NAM-expanded NK cells achieves objective clinical responses in patients with relapsed/refractory non-Hodgkin lymphoma[12]. It should be emphasized that this benefit is derived from ex vivo metabolic conditioning of cultured NK cells and cannot be generalized to oral nutritional supplementation of NAM in patients. Despite encouraging translational evidence in adoptive cell therapy, no randomized controlled trials have validated oral nutritional supplementation as an in vivo immune adjuvant to boost endogenous NK cell function during standard immunotherapy for solid tumors.

B-cell mediated vitamin responses in cancer

Vitamins can alter B-cell differentiation, cytokine production, and antigen-presenting functions within the TME. Because B cells can support either anti-tumor immunity or regulatory programs, the net effect is context-dependent. Vitamin-mediated B-cell effects are also bidirectional. RA and vitamin D signaling can promote regulatory or suppressive B-cell states in defined experimental systems, whereas vitamin E can enhance antibody responses[3,50]. The relevance of these effects to intratumoral B-cell function during ICI therapy remains uncertain.

Population-level vitamin D studies have reported associations with cancer mortality or selected cancer outcomes, but these analyses generally lack tumor immune profiling and cannot establish that B-cell remodeling mediates the observed associations. Consequently, vitamin D should not be presented as a validated B-cell-directed cancer therapy.

To date, no prospective randomized controlled trials have specifically evaluated how standardized vitamin A, D, or E supplementation remodels intratumoral B cell subsets or improves ICI efficacy in cancer patients. Current vitamin D intervention trials only report general tumor incidence and survival outcomes, lacking predefined B cell-related immune biomarkers. Rigorous interventional studies are still required to validate the clinical potential of vitamin-based B cell immunomodulation in tumor treatment. Many reported retinoid- and vitamin D-driven B-cell regulatory phenotypes are initially characterized in infectious or mucosal immune contexts; their performance within the TME requires further dedicated tumor-focused validation.

T-cell mediated vitamin responses in cancer

Vitamins can affect T-cell differentiation, exhaustion, and effector function, but the direction of these effects depends on dose, receptor signaling, tissue context, and treatment sequence[3,50]. CD8⁺ cytotoxic T lymphocytes and CD4⁺ helper T cells are major components of durable anti-tumor responses. RA signaling can support selected tumor-specific T-cell programs, whereas sustained or supraphysiological retinoid exposure may promote regulatory T-cell differentiation under defined conditions[4,51]. Thus, retinoid activity should be interpreted as pathway- and context-dependent rather than intrinsically immunostimulatory. Vitamin C remodels T-cell function through epigenetic and post-translational mechanisms. As an essential cofactor for TET enzymes, vitamin C can influence DNA demethylation and T-cell state, while vitamin C-dependent STAT1 lysine vitcylation has been reported to sustain interferon signaling and enhance MHC-I antigen presentation in preclinical models[2,15]. The latter mechanism remains an exploratory biomarker and has not been clinically validated. In preclinical immune models, 1,25(OH)₂D₃ can suppress selected pro-inflammatory T-cell programs and alter Treg/Th17 balance[3,52]. Vitamin K isoforms have also been reported to affect T-cell proliferation and regulatory phenotypes, but the cancer-specific evidence is limited and should not be generalized across K1, K2, and K3[53,54].

All aforementioned T cell regulatory mechanisms and combinatorial immunotherapeutic synergies are validated only in vitro cell cultures and murine tumor models. The STAT1 vitcylation modification remains an exploratory preclinical biomarker without human specimen verification.

Observational cohort studies, including mixed retrospective-prospective analyses, have reported associations between adequate baseline serum 25(OH)D and improved objective response rates, prolonged progression-free survival, and reduced immune-related colitis in anti-PD-1-treated patients[11,21]. Because these observational associations are vulnerable to confounding by baseline inflammation, nutritional status, and concurrent systemic therapy, they cannot establish causal vitamin D-mediated T-cell reprogramming in the clinical setting.

Phase I/II prospective trials of ATRA combined with pembrolizumab in metastatic melanoma have suggested that retinoid intervention may repolarize suppressive myeloid cells, restore intratumoral T cell activity, and induce durable clinical responses in partial patient subsets[10,19]. The prospective observational PROVIDENCE study reported that systematic vitamin D repletion was associated with improved clinical outcomes and reduced thyroid immune-related adverse events in patients with advanced cancer receiving ICIs; as a non-randomized cohort design, this does not establish causality[20]. Nevertheless, no phase III multicenter randomized controlled trials have established universal clinical benefits of ATRA or vitamin D adjuvant supplementation across solid tumor types. In addition, prospective trials evaluating fixed high-dose intravenous vitamin C plus anti-PD-1 regimens for lung cancer patients remain absent.

NEGLECTED VITAMIN FAMILIES: B VITAMINS AND VITAMIN K IN TUMOR IMMUNOREGULATION

Compared with vitamins A, C, D, and E, which have received comparatively greater attention for their direct effects on immune signaling, redox regulation, differentiation, and transcriptional control, vitamins B and K remain relatively underexplored in the context of tumor immunoregulation. Rather than acting primarily through a single canonical immunological pathway, B and K vitamins exert their effects through diverse metabolic, enzymatic, redox, and signaling processes that are closely intertwined with cellular state and the TME. Their immunological consequences may therefore vary substantially according to vitamin isoform, cellular context, metabolic status, and disease stage. This context dependence, together with the limited clinical and mechanistic evidence currently available, has contributed to their comparatively overlooked roles in cancer immunology. Nevertheless, emerging evidence suggests that B and K vitamins may influence immune-cell metabolism, inflammatory signaling, oxidative homeostasis, and tumor-immune interactions, highlighting their potential as context-dependent modulators of anti-tumor immunity.

Distinct and context-dependent immunological roles of B vitamins

B vitamins comprise a group of water-soluble micronutrients that function primarily as coenzymes or metabolic precursors in essential cellular processes. They are closely integrated with immune-cell metabolism through their roles in flavin-dependent redox reactions, coenzyme A synthesis, one-carbon metabolism, and NAD⁺ homeostasis, thereby influencing cellular energy production and immune-cell function. Their immunological effects are highly dependent on vitamin isoform, cellular context, and nutritional or metabolic status. Although B vitamins are essential for maintaining immune-cell fitness, evidence that routine systemic supplementation enhances ICI efficacy remains limited. Caution should be exercised when extrapolating immunological observations derived from infection or non-oncological experimental settings to tumor-bearing human patients.

Riboflavin (vitamin B2): Riboflavin is the precursor of flavin adenine dinucleotide and flavin mononucleotide and therefore supports mitochondrial and redox metabolism. Experimental cancer studies suggest that B2 availability can influence immune-cell metabolic programs[55], but direct evidence that B2 supplementation improves anti-tumor immunity in patients remains insufficient. Potential benefit is therefore best framed as correction of deficiency or metabolic support rather than a validated anti-tumor intervention.

Pantothenic acid (vitamin B5): Vitamin B5 is required for coenzyme A synthesis and supports fatty-acid metabolism and cellular energy metabolism. Preclinical findings implicate B5 in innate and adaptive immune regulation, although cancer immunotherapy-related evidence remains sparse.

Pyridoxine (vitamin B6): Vitamin B6 participates in amino-acid metabolism and one-carbon and inflammatory pathways. Cancer-focused literature suggests that B6-dependent metabolism may influence immune-cell function and antitumor immunity[56]. However, the direction of immune effects is context-dependent, and there is currently no basis for recommending high-dose B6 supplementation as a general immunotherapy adjuvant.

Folic acid (vitamin B9): Folate supports nucleotide synthesis and one-carbon metabolism required for lymphocyte proliferation and epigenetic maintenance. Folate sufficiency is important for normal immune-cell function, but the relationship between folate exposure and cancer is bidirectional and can depend on timing and tumor genotype[56,57]. Thus, deficiency correction should be distinguished from supraphysiological supplementation, particularly in tumors with altered nucleotide or DNA-repair metabolism.

NAM (vitamin B3 derivative): NAM contributes to NAD⁺ metabolism and thereby affects sirtuins, PARP activity, redox balance, and cellular stress responses. Among B-vitamin-related interventions, NAM has one of the strongest translational signals in cellular immunotherapy: Ex vivo NAM conditioning improves NK-cell metabolic fitness, persistence, and cytotoxicity, with clinical responses reported in relapsed/refractory non-Hodgkin lymphoma[12]. This should not be conflated with evidence for routine oral nutritional supplementation of NAM during ICI therapy.

Distinct and bidirectional immunological profiles of vitamin K isoforms (K1, K2, K3)

Vitamin K should be retained in this review because its isoforms illustrate an important boundary condition of the precision-vitamin framework: Not every vitamin is expected to function as a direct immune activator. K1 is primarily a coagulation-related nutrient; K2 has emerging links to inflammatory and tumor biology; and K3 is a synthetic redox-active compound with a narrow therapeutic window. These distinct profiles argue against treating vitamin K as a single immunological entity[58].

Phylloquinone (vitamin K1): Vitamin K1 primarily supports hepatic γ-carboxylation of coagulation proteins. Its direct role in tumor immune reprogramming is poorly defined. In oncology, maintaining adequate K1 status may be relevant to coagulation management[59-61], but this supportive role should not be presented as evidence of direct anti-tumor immune activation.

Menaquinone (vitamin K2, MK series): Vitamin K2 has attracted interest because experimental studies have linked it to inflammatory signaling, including nuclear factor kappa B/STAT3-related pathways and TAM phenotypes[62]. Epidemiological observations concerning dietary vitamin K and cancer risk remain inconsistent and cannot establish therapeutic efficacy[63]. Accordingly, K2 should be described as an emerging mechanistic candidate rather than a clinically validated immune adjuvant.

Menadione (vitamin K3): Menadione (vitamin K3) is a synthetic naphthoquinone with redox activity and can induce oxidative stress and tumor-cell death in experimental systems. Its translational potential is constrained by toxicity and a narrow therapeutic window[64]. It therefore represents a pharmacological redox probe rather than a nutritional intervention and should not be grouped with routine vitamin K supplementation.

Translational limitations and future research outlook for B vitamins and vitamin K: The major translational barriers for B vitamins and vitamin K are insufficient dose-response data, limited tissue-level biomarkers, uncertainty about treatment sequence, and a lack of randomized trials using contemporary ICI endpoints[65]. These barriers and the corresponding research agenda-biomarker validation, exposure-response profiling, and randomized trials with pre-specified immune endpoints-are elaborated in below.

CLINICAL TRANSLATION OF VITAMIN-BASED IMMUNOTHERAPY: EVIDENCE STATUS, LIMITATIONS AND BIOMARKER-DRIVEN PATIENT-SELECTION STRATEGY

Clinical translation of vitamin-based immunotherapy remains at an early and heterogeneous stage. Rather than supporting a universal benefit of vitamin supplementation, current evidence favors context-dependent interventions defined by biological rationale, exposure, and patient characteristics.

Current and historical clinical evidence and limitations

Several vitamin-related strategies have generated early clinical or translational signals. ATRA combined with pembrolizumab has shown activity in metastatic melanoma, while vitamin D studies in patients receiving ICIs have reported associations between vitamin D status and treatment outcomes or immune-related toxicities[10,11,19-21]. NAM has also been incorporated into ex vivo NK-cell manufacturing, representing a distinct translational approach in which vitamin-derived metabolites are used to optimize cellular products rather than administered as systemic supplements[12]. Other approaches, including pharmacological ascorbate and vitamin E-SHP1 pathway modulation, remain under investigation[7,9,14,15]. However, these signals differ substantially in study design, intervention type, exposure, and clinical endpoints. Observational associations cannot establish causality, and early clinical activity does not necessarily demonstrate improved survival or durable benefit. Moreover, relatively few studies have directly evaluated vitamins as defined combination partners for immune checkpoint blockade.

Historical vitamin trials provide useful information on biological activity and potential safety concerns, but their relevance to contemporary immunotherapy is limited. Most were designed for nutritional prevention, deficiency correction, or conventional cancer treatment rather than biomarker-defined immune modulation. Three differences are particularly important. First, exposure is not equivalent across interventions: Dose, route, absorption, and pharmacokinetics can produce markedly different biological concentrations. Notably, outcomes observed from ex vivo cell-culture conditioning, nutritional supplementation, and pharmacological high-dose interventions cannot be directly interchanged. Second, patient populations were generally not biologically stratified, making it difficult to identify subgroups that might benefit from or be harmed by a specific intervention[11]. Third, treatment context and endpoints differed, with historical studies rarely incorporating immune monitoring or pharmacodynamic markers relevant to ICI therapy. Therefore, historical trials should primarily inform hypothesis generation, exposure boundaries, and safety considerations rather than serve as direct evidence for modern vitamin-ICI combinations.

A targeted registry search also illustrates an important translational gap: Ongoing human studies directly linking vitamin exposure to immunotherapy remain limited. As of June 2026, NCT04615988 was recruiting adults with advanced cancer receiving standard PD-1/PD-L1-based immunotherapy to examine whether baseline serum 25(OH)D is associated with endocrine immune-related toxicity and treatment response; importantly, this is a prospective observational study rather than a vitamin-intervention trial. NCT07241585 was also recruiting patients with nonmelanoma skin cancer in a randomized study of vitamin D plus photodynamic therapy, with tumor immune-microenvironment endpoints. These studies are informative for biomarker and mechanism development but should not be interpreted as evidence that vitamin supplementation has established efficacy as an ICI combination.

Biomarker-guided patient selection for vitamin-based immunotherapy

The context-dependent nature of vitamin activity provides a rationale for biomarker-guided patient selection. Rather than using vitamin status as a single criterion, future studies should integrate complementary biomarkers that address nutritional need, therapeutic exposure, tumor susceptibility, and immune responsiveness.

Baseline vitamin status may help distinguish patients who require nutritional repletion from those who may be candidates for pharmacological vitamin intervention. Pharmacokinetic and pharmacodynamic markers can further determine whether the intended exposure is achieved and whether the relevant biological pathway is engaged. Tumor and metabolic features, including oncogenic drivers, transporter expression, metabolic dependencies, and redox state, may help identify tumors with greater sensitivity to specific vitamin-based interventions[66]. Immune-context features, such as myeloid-cell composition, T-cell functional states, and NK-cell activity, may further indicate whether vitamin-mediated immune modulation is biologically relevant.

These biomarkers should not be interpreted independently. Their clinical utility will depend on the treatment context, including disease stage, therapeutic combination, dose, route of administration, and timing of vitamin exposure. A practical framework is therefore to determine whether vitamin intervention is needed, whether adequate exposure is achieved, whether the intended biological pathway is engaged, and whether this translates into clinical benefit or toxicity.

This framework shifts vitamin therapy from empirical supplementation toward precision intervention. The key clinical question is therefore not whether vitamins are broadly beneficial, but which patient is most likely to benefit from which vitamin-based intervention, at what exposure, and in which therapeutic context.

PERSPECTIVES AND FUTURE RESEARCH PRIORITIES

Concluding summary of current understanding

This review conceptualizes vitamins as context-dependent immunometabolic regulators in the TME, instead of generic dietary cofactors or universal antioxidants. Vitamin-related signaling shapes anti-tumor immune outputs via metabolic reprogramming, epigenetic remodeling and post-translational protein modification. A single vitamin may either potentiate cytotoxic anti-tumor immunity or drive immune tolerance, which is governed by dose, administration route, tissue compartment and tumor-intrinsic features. None of the vitamin-based intervention strategies reviewed herein have been established as general-purpose adjuvants for ICI therapy.

Biomarker readiness and translational status

Biomarker evaluation must discriminate clinically validated readouts from promising yet unvalidated mechanistic candidates[67]. Serum 25(OH)D represents the most feasible clinical assay to assess vitamin D nutritional status[68], while STAT1 vitcylation, SCARB1-SHP1 signaling, ALDH activity, GLUT1-dependent DHA transport, and NK-cell metabolic fitness remain exploratory biomarkers[15]. Figure 2 is therefore conceptual rather than clinically actionable for patient decision-making.

Preclinical findings support stratified, research hypothesis biomarker-guided vitamin adjuvant intervention, termed precision vitamin immunotherapy, which tailors vitamin regimens to individual immune profiles[7]. This framework remains a translational hypothesis: Most candidate biomarkers have only been characterised in preclinical models, lacking prospective clinical validation, standardised cutoffs, and confirmed predictive performance in patients receiving immunotherapy.

Several assay-specific obstacles limit translation of this individualised strategy. Confounding variables including dietary intake, hepatic and renal function, concurrent medications, and gut microbiota distort biomarker measurements and hinder consensus cutoff establishment. Furthermore, few prospective interventional trials clarify whether biomarker-directed vitamin dosing improves objective response rate, progression-free survival, or overall survival in patients treated with chemo-, radio-, or immunotherapy.

In summary, research hypothesis biomarker-guided vitamin intervention holds promise but is not ready for routine clinical implementation. 25(OH)D is best utilised to define vitamin D status and stratify patients, rather than serve as an independent predictor of ICI response[69]. Prospective cohorts and randomised trials are required to establish clinically relevant cutoffs, exposure windows, treatment sequencing, and eligible patient subgroups.

Knowledge gaps and future research priorities

Five core priorities should guide the advancement of vitamin-mediated tumor immunotherapy: (1) Prospective validation of candidate biomarkers. Assays, standardized threshold values, and predictive performance must be prospectively determined for the exploratory biomarkers outlined in the preceding subsection Distinction should be maintained between nutritional status markers and predictive treatment-response biomarkers. Graphical or tabulated evidence-level stratification (pre-clinical mechanistic data/retrospective observational cohorts/phase I-II interventional studies/phase-III randomized controlled trials/ongoing registered trials) should be adopted in future reports to avoid over-interpretation of preliminary findings; (2) Formal pharmacokinetic-pharmacodynamic profiling. Rigorously characterize exposure-response relationships for vitamins used for pharmacological modulation (e.g., intravenous ascorbate, retinoid-pathway modulators)[70,71] (Table 3). Explicitly separate physiological deficiency correction from drug-like high-dose pathway modulation, as these two strategies may yield divergent immune outputs; (3) Systematic evaluation of treatment-related variables. Prospectively test dose ranges, administration routes, and therapeutic sequencing (vitamin intervention relative to ICI, vaccine or adoptive cell therapy). Avoid generalized classwide assumptions for each vitamin; (4) Well-designed randomized controlled clinical trials with pre-specified immune endpoints. Trials should incorporate modern ICI comparators, predefined immune readouts rather than only survival endpoints. Current evidence base is uneven across vitamin subtypes: Vitamins A, C, D, E have abundant mechanistic data; in contrast, B-complex vitamins and vitamin K require deeper mechanistic investigation to balance the scope of broad-theme reviews. For vitamin K isoforms, distinct biological functions of K1, K2 and K3 must not be conflated; future work should clarify whether any isoform can drive meaningful anti-tumor immune reprogramming beyond coagulation-related supportive effects[59,60]; and (5) Stratification by patient and tumor features. Patient cohorts should be stratified according to tumor subtype, intratumoral immune contexture, tumor metabolic phenotype and baseline nutritional/vitamin status. Such stratification helps disentangle nutritional support from genuine immunomodulatory therapeutic effects and prevents pre-clinical hypotheses from being misrepresented as clinically validated strategies. Collectively, the precision vitamin-mediated immunotherapy framework offers a promising conceptual paradigm. Real-world clinical implementation, however, still hinges on addressing above-mentioned knowledge gaps through well-powered prospective experimental and interventional studies.

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.

Safety, drug-interaction and contraindication considerations

Vitamin interventions are not risk-free, particularly at pharmacological (drug-like) exposures; physiological nutritional repletion is generally well tolerated, whereas high-dose strategies require screening, monitoring, and explicit contraindication review.

Vitamin A/retinoids: Pharmacological ATRA carries teratogenic risk (contraindicated in pregnancy; effective contraception required), mucocutaneous toxicity, hypertriglyceridemia, transaminase elevations, and pseudotumor cerebri (risk increased by concomitant tetracyclines); concurrent retinoids or high-dose vitamin A are contraindicated[10,19,71]. The differentiation syndrome of high-dose APL use is not expected at the low doses used in the ATRA-plus-pembrolizumab setting, but lipid monitoring remains advisable[10,19].

Vitamin C (high-dose intravenous): G6PD deficiency is a contraindication because of acute hemolysis risk-G6PD screening is recommended before pharmacological dosing[72-74]. Caution is required in renal impairment, calcium-oxalate stone history (oxalate nephropathy), and iron overload; very high doses may also modulate warfarin response and interfere with point-of-care glucose readings[72,74].

Vitamin D: Supraphysiological doses cause hypercalcemia/hypercalciuria, nephrocalcinosis, and stones; contraindications include hypercalcemia, calcium nephrolithiasis, and granulomatous disorders (e.g., sarcoidosis, where hypercalcemia risk is increased)[75]. Thiazides raise hypercalcemia risk; glucocorticoids antagonize vitamin D, cholestyramine/orlistat/phenytoin reduce its effect[75].

Vitamin E: High doses have antiplatelet/anti-vitamin K effects and are associated with increased hemorrhagic-stroke risk; the SELECT trial reported 17% higher prostate cancer incidence at 400 IU/day[76,77]. Use nutritional doses only in patients on warfarin/antiplatelets; discontinue high doses perioperatively[76,77].

Vitamin K: K1/K2 antagonize vitamin K antagonists (warfarin), causing international normalized ratio (INR) instability in oncology patients on vitamin K antagonists[60,61]. K3 (menadione) has a narrow therapeutic window, caused hemolysis and neonatal kernicterus, and is withdrawn from clinical use-a pharmacological redox probe, not a supplement[78].

B vitamins: High-dose folate can mask vitamin B12 deficiency and allow neurological damage to progress[79]; high-dose B6 causes peripheral sensory neuropathy[80]; high-dose NAM (≥ 3 g/day) carries hepatotoxicity risk (worse with nicotinic acid)[36,81]. Ex vivo NAM use in NK manufacturing is not equivalent to oral supplementation[12].

Overall, antioxidants may also blunt ROS-dependent therapy in some contexts (as discussed above). Pre-treatment screening (G6PD before intravenous ascorbate; serum calcium before vitamin D; bleeding risk before high-dose E/K), monitoring (lipids during ATRA; calcium during vitamin D; INR in vitamin K antagonist patients; liver enzymes with high-dose B3), and contraindication review are therefore mandatory in any future clinical evaluation.

Practical implementation considerations

Even if promising biomarker-vitamin pairings are identified in future studies, real-world clinical implementation faces multiple practical obstacles. Candidate exploratory biomarkers (STAT1 vitcylation, SCARB1-SHP1 signaling, ALDH activity) currently lack commercially available, standardized clinical assays. In addition, treatment feasibility varies across healthcare settings: High-dose intravenous ascorbate requires infusion facilities, whereas oral nutritional repletion is more broadly accessible. Baseline vitamin status also shows large geographic and inter-patient heterogeneity, which should be considered when designing future interventional trials.

CONCLUSION

This review conceptualizes vitamins as context dependent immunometabolic regulators within the TME, rather than simple dietary cofactors or universal antioxidants. Vitamin dependent signaling orchestrates immune-cell proliferation, activation, infiltration, differentiation, T-cell exhaustion and antigen presentation. Beyond redox homeostasis, vitamins exert regulatory functions via metabolic reprogramming, epigenetic remodeling, post-translational protein modification and checkpoint-like signaling. This pleiotropy explains why an identical vitamin can augment cytotoxic anti-tumor immunity under one set of conditions yet reinforce immune tolerance in another. The collective pre-clinical and correlative clinical data motivate the framework of precision vitamin-guided immunotherapy, yet substantial translational barriers remain before clinical adoption.