Physical exercise confers systemic immunomodulatory benefits, yet the molecular mediators linking metabolic stress to immune cell reprogramming remain incompletely defined. N-lactoyl-phenylalanine (Lac-Phe), a lactate-phenylalanine conjugate synthesized by carnosine dipeptidase 2 (CNDP2), has emerged as a critical exercise-derived metabolite that bridges peripheral energy metabolism with central and peripheral immune regulation. This review systematically summarizes the biosynthetic regulatory network of Lac-Phe, with emphasis on its immunomodulatory functions. And translational advances include biomimetic scaffolds enabling localized Lac-Phe release for tissue regeneration and the first human clinical trial (NCT06743009) evaluating its metabolic and immunomodulatory efficacy. Nevertheless, the unidentified direct membrane receptor on immune cells, unaddressed safety risks of long-term immune modulation, and immature immune-targeted delivery approaches impede clinical translation. Future priorities should focus on receptor identification through chemical proteomics and CRISPR screening, determination of the pharmacological safety window for chronic immunomodulation, and development of localized delivery strategies to accelerate clinical application in immune-mediated disorders.
The anti-tumor immune response includes both acquired and innate immunity, with T cells playing a central role. Recent advances in immunotherapy have shown great promise, but only a small percentage of patients benefit. The low efficacy of immunotherapy is often linked to the tumor microenvironment (TME), which hampers immune responses. Tumor cells undergo metabolic reprogramming, significantly affecting the TME and immune cell function. Tumor cells not only deplete nutrients from the TME, limiting immune cell activation, but also accelerate the efflux of metabolites, further suppressing immune responses. Additionally, the poor vascularization and low material exchange in the TME result in metabolite accumulation, which inhibits immune cell activation. Tumor-specific metabolic pathways can also evade immune surveillance by reducing the immune system's constraints on tumor tissue. This article focuses on the roles of key metabolic pathways, such as aerobic glycolysis, lipid metabolism, and amino acid metabolism, in tumor immunity. Understanding the relationship between tumor metabolism and anti-tumor immunity is crucial for developing more effective therapeutic strategies, including improving immune response efficiency by modulating nutrient flow and reducing the adverse effects of metabolites.
The adoptive infusion of natural killer (NK) cells is a promising immunotherapy for cancer, viral infections, and aging-associated diseases. Clinical responses have been linked to enhanced cytotoxicity and sustained NK cell persistence in vivo. While preconditioning and/or cytokines support improvement in vivo persistence of infused NK cells. However, the effects of ex vivo expanded natural killer (eNK) cells infusion on peripheral blood NK cells-without these interventions-remain unclear. This study analyzed peripheral blood NK cell phenotypes and functions using flow cytometric analysis and Tarascan VP system in healthy subjects. Results showed that autologous eNK cells infusion transiently increased in NK cell proportions and altered subsets and functions. Notably, CD56bright NK cells significantly increased on day 1, accompanied by upregulated expression of activating receptors (NKG2D, NKp30), cytolytic molecules (perforin, granzyme B), and the degranulation marker CD107. By day 7, CD56dim NK cells increased, with significantly enhanced NK cell activity in peripheral blood. These findings indicate that eNK cells infusion induces transient phenotypic and functional changes in peripheral blood NK cells, enhancing their activity in vivo. This study provides insight into optimizing adoptive NK cell therapies to improve therapeutic efficacy.
