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

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.

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.

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.