Vitamin D continues to emerge as a pleiotropic regulator of immune and metabolic homeostasis, operating at the crossroads of endocrine, skeletal, and immune systems (4–6). Traditionally recognized for its role in calcium–phosphate balance and bone mineralization, vitamin D—functioning both as a vitamin and a pre-hormone—exerts wide-ranging biological effects through its active metabolite, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] (7–10). This metabolite binds to the vitamin D receptor (VDR), a ligand-dependent nuclear transcription factor expressed in numerous immune and non-immune cells, including those in the intestine, pancreas, bone, and skin (11). Upon activation, the 1,25(OH)₂D₃–VDR complex forms a heterodimer with the retinoid X receptor (RXR-α) and binds to vitamin D response elements (VDREs) in target genes, thereby regulating transcriptional programs involved in cell proliferation, differentiation, cytokine secretion, and immune tolerance (12–15).

Physiologically, vitamin D is synthesized in the skin from 7-dehydrocholesterol upon exposure to ultraviolet B radiation (290–320 nm) and subsequently hydroxylated in the liver and kidney by CYP2R1 and CYP27B1 to generate its active form (16, 17). The expression of these metabolic enzymes and the VDR within immune and non-immune tissues underscores the body’s intrinsic capacity to locally produce and respond to calcitriol, thereby modulating both autocrine and paracrine signaling networks. Beyond its classical skeletal actions, vitamin D plays critical roles in neuromuscular function and in regulating key cellular processes such as growth, differentiation, apoptosis, and glucose metabolism (18–25). Collectively, these multidimensional effects position vitamin D as a central integrator of immune regulation, metabolic balance, and overall systemic health.

In immunology, the terms immunomodulation and immune regulation are often used interchangeably, yet they represent distinct biological concepts.

Immune regulation refers to the intrinsic, homeostatic mechanisms by which the immune system maintains balance between activation and tolerance (26–28). These include key processes such as central and peripheral tolerance, the action of regulatory immune cells, cytokine feedback loops, and the suppression of excessive or self-reactive immune responses (29–31). In essence, immune regulation ensures the preservation of immune equilibrium and self-tolerance under physiological conditions. By contrast, immunomodulation encompasses any external or endogenous intervention—pharmacological, nutritional, hormonal, or microbial—that alters immune activity, either by enhancing or suppressing or redirecting specific cellular functions (32–34). Immunomodulators can therefore act as stimulants, suppressants, or balancing agents depending on the immunological context (Figure 1).

Through interconnected pathways, vitamin D acts as a pivotal modulator of both innate and adaptive immunity. It strengthens antimicrobial defenses by inducing the expression of potent effector peptides, including cathelicidin and β-defensin 2, while simultaneously attenuating excessive inflammation by downregulating proinflammatory mediators (35–37). By fine-tuning cytokine networks and antigen-driven responses, vitamin D maintains a delicate equilibrium between immune activation and tolerance, promoting resolution of inflammation and preserving tissue integrity and homeostasis. Vitamin D thus exemplifies a potent immunomodulatory agent, as it influences both regulatory and effector immune mechanisms (38). It does not merely suppress or activate immune functions, but rather modulates their intensity and quality, promoting an adaptive state of functional equilibrium that is essential for immune homeostasis. In this regard, vitamin D serves as a paradigm of context-dependent immunomodulation (39)—a molecular sentinel that operates through finely regulated receptor-mediated signaling to maintain immune homeostasis.

The experimental study by Meterfi et al. reveals how environmental factors dynamically shape vitamin D-mediated immune regulation. By exposing peritoneal macrophages to UVB radiation with or without a simulated passive barrier, the authors demonstrate that UVB enhances respiratory burst, MPO expression, and M1-like polarization, while physical shielding fine-tunes these effects by attenuating METosis-related MPO activity and modulating local redox metabolism. This study highlights how physical environmental constraints can calibrate vitamin D metabolism and innate immune effector functions, providing mechanistic insight into how external cues orchestrate immune homeostasis.

Allergic disease receives careful attention: the review by Zhang et al. synthesizes mechanistic and clinical evidence linking vitamin D to atopic dermatitis, allergic rhinitis and asthma. In a complementary piece, Zúñiga and Bazan-Perkins analyze the controversial relationship between vitamin D and atopy, highlighting that vitamin D promotes a pro-tolerogenic Th2 phenotype, suppresses Th1-driven inflammation, and supports immune homeostasis. They further emphasize that vitamin D acts through regulatory T-cells to maintain cytokine balance—modulating both pro- and anti-inflammatory pathways—and by limiting B-cell proliferation and differentiation, thereby fostering a state of immune equilibrium.

In obstetric immuno-hematology, the clinical study by Wang et al. shows that gestational hypertension is associated with lower vitamin D levels and platelet counts (PLT), along with higher mean platelet volume (MPV), platelet distribution width (PDW), and D-dimer levels. Vitamin D was significantly correlated with these parameters, suggesting a potential role in modulating platelet function and coagulation, and highlighting the value of optimizing vitamin D status in managing this condition.

The role of vitamin D during the COVID-19 pandemic is examined from multiple complementary angles. Missilmani et al. report that while systemic serum 25(OH)D levels alone are not directly associated with COVID-19 status, elevated nasopharyngeal VDR and DEFA1–3 expression correlate with reduced risk of SARS-CoV-2 infection, underscoring the importance of local vitamin D responsiveness. Complementing these findings, Petakh et al., in an umbrella review of systematic reviews, conclude that vitamin D supplementation significantly reduces the risk of Intensive Care Unit (ICU) admissions and mortality in COVID-19, particularly in vitamin D–deficient populations, while underscoring the need for standardized study designs. The cohort study by Konikowska et al. further establishes that sufficient vitamin D levels (≥30 ng/mL) are associated with improved survival and a reduced risk of death among hospitalized COVID-19 patients, highlighting the prognostic value of 25(OH)D concentrations during hospitalization. In pediatric settings, Perestiuk et al. demonstrate that vitamin D deficiency or insufficiency is associated with more severe acute disease, prolonged hospitalization, and a 2.2-fold higher risk of long COVID—particularly with neurological and musculoskeletal symptoms—underscoring the importance of age-specific preventive approaches.

Population and clinical cohort studies add epidemiological weight to mechanistic findings. Liu et al. report that lower serum 25(OH)D is associated with a higher incidence of hyperlipidemia in adults, highlighting the link between lifestyle-related vitamin D insufficiency and adverse lipid profiles. In the inflammatory bowel disease field, Zheng et al. report that higher baseline vitamin D levels independently predict clinical remission in infliximab-treated Crohn’s disease patients, suggesting that vitamin D status may influence biologic therapy outcomes and patient stratification.

In their Opinion article, Su et al. revisit the debated field of high-dose vitamin D supplementation as a potential approach to immune recalibration in autoimmune diseases, highlighting its capacity to modulate Th1, Th17, and regulatory T-cells, alongside B-cell activity, in selected conditions, including multiple sclerosis, systemic lupus erythematosus, and Crohn’s disease. Adding a genetic perspective, Huang et al. applied a Mendelian randomization framework leveraging genetic variants linked to various circulating micronutrients, including vitamin D, to dissect causal relationships with systemic lupus erythematosus (SLE). Using summary statistics from the IEU OpenGWAS database and supported by multiple sensitivity analyses (including MR-PRESSO, MR-Egger, and leave-one-out), their findings provide genetic evidence for a protective role of selected nutrients—notably vitamin D and calcium—against autoimmune susceptibility, highlighting the value of integrative nutrigenomic approaches.

Two studies in this volume shed light on novel oncological applications of vitamin D. Zhang et al. reveal an immunosuppressive 1,25(OH)₂D₃–LL-37–tumor-associated macrophage (TAM) axis in hepatocellular carcinoma (HCC), in which LL-37 induction promotes macrophage recruitment and M2 polarization, thereby limiting vitamin D’s efficacy. Importantly, the authors show that suramin, an LL-37 inhibitor, disrupts TAM recruitment and M2 polarization, restores M1 polarization, inhibits protein kinase B/mammalian target of rapamycin (Akt/mTOR) and signal transducer and activator of transcription 3 (STAT3) signaling, and enhances 1,25(OH)₂D₃ therapeutic effects, reducing tumor growth and nodules in vivo, highlighting its potential as an adjunct in vitamin D–based immunotherapy for HCC.

To overcome the narrow therapeutic window of vitamin D₃ in oncology, Ezcurra-Hualde et al. developed a liposomal cholecalciferol formulation (VD-LP) with high encapsulation efficiency and long-term stability. VD-LP modulated immune-related and metabolic gene expression in THP-1 cells and exerted superior antiproliferative effects across colorectal, breast, and prostate cancer cell lines compared to free vitamin D₃. In vivo, VD-LP delayed tumor growth and improved survival without inducing hypercalcemia, highlighting its favorable toxicity profile. These findings demonstrate how nanotechnological innovations can safely extend vitamin D’s therapeutic applications in oncology field.