Abstract
Nutritional immunity is a major facet of host defense, wherein the host immune system strategically limits pathogen access to critical nutrients, including iron, zinc, vitamins, lipids, and amino acids, to repress microbial proliferation and virulence. This review provides a comprehensive synthesis of the molecular mechanisms that power nutrient immunity, including metal homeostasis, nutrient competition, transporter modulation, hormonal regulation, and direct antimicrobial actions. We examine nutrient-specific strategies employed by the host, such as iron-withholding mechanisms, vitamin deprivation, and copper-mediated toxicity. We also explore how diverse pathogens, including extracellular, intracellular, and eukaryotic pathogens, adapt to these hostile nutritional landscapes through siderophore diversification, regulatory integration, and metabolic rewiring. Comparative genomic analyses reveal convergent evolution in nutrient acquisition systems, illuminating the dynamic arms race between host restriction and microbial evasion. We examine the immunological mechanisms that regulate nutritional immunity. Further, we discuss the translational potential of nutritional immunity, cutting across nutrient-based therapies, host-directed interventions, and emerging diagnostic biomarkers. Finally, we suggest future directions that synergize nutritional immunity with microbiome ecology, global malnutrition, and personalized medicine. By elucidating the interconnection between metabolism and immunity, this review highlights the therapeutic promise of starving or toxifying the pathogen to save the host.