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

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.