Personalized nutrition, guided by nutrigenetic insights, is a promising strategy for optimizing immune function through targeted dietary interventions. Peripheral blood mononuclear cells (PBMCs), comprising lymphocytes and monocytes, serve as a dynamic model for investigating gene-diet interactions because of their sensitivity to nutritional and genetic influences. This review aimed to synthesize current reports on the interplay between genetic variation, dietary components, and PBMC molecular responses and evaluate the clinical applicability of the interaction in the development of individualized nutritional strategies for immune optimization. A structured and narrative-focused method was used to synthesize the literature, showing the relationship between molecular knowledge and practical solutions in personalized nutrition as well as immune system optimization, with a focus on PBMCs. A thorough search was performed on PubMed, Scopus, and Google Scholar, encompassing the years 2006 to 2025. Genetic polymorphisms in the vitamin D receptor (VDR), peroxisome proliferator-activated receptor (PPAR), superoxide dismutase 2 (SOD2), and Toll-like receptor 4 (TLR4) modulated the response of PBMCs to nutrients, including vitamin D, omega-3 fatty acids, antioxidants, and polyphenols. The discussion encompassed molecular pathways involving cytokine modulation, oxidative stress, and epigenetic alterations, highlighting PBMCs as indicators of immunological resistance and chronic disease susceptibility. The exploration of multiomics integration to achieve precision nutrition holds significant implications for clinical practice and public health. By using PBMC-based nutrigenetic profiling as a monitoring and stratification tool, future interventions may move toward more focused immune optimization and improved health outcomes, pending further validation in longitudinal and interventional studies.