Metadichol Drives NK Cell Maturation via A CD122/IL-15 Signaling Through NF-κB-Independent Pathways

Background: Natural killer (NK) cells are essential innate immune effectors with significant therapeutic potential in cancer immunotherapy. However, strategies to enhance NK cell maturation and effector function remain limited. Metadichol, a nano-emulsion of policosanol capable of modulating 49 nuclear receptors, has demonstrated immunomodulatory properties, yet its effects on NK cell developmental programming have not been systematically characterized. Understanding how Metadichol regulates NK cell maturation, particularly through the critical IL-15/CD122 signaling axis, could reveal novel immunotherapeutic approaches.Methods: Human peripheral blood mononuclear cells (PBMCs) were treated with Metadichol at concentrations ranging from 0.1 pg/ml to 100 ng/ml. Expression of 19 genes critical for NK cell development, including surface markers, transcription factors, and cytokine receptors, was analyzed by qRT-PCR. Regulatory network analysis was performed to elucidate mechanistic pathways, with particular focus on IL-15 signaling and NF-κB-independent regulatory mechanisms.Results: Metadichol induced a coordinated "push-pull" developmental program characterized by dramatic upregulation of mature NK cell markers concurrent with suppression of early progenitor markers. CD122 (IL-2Rβ), the essential receptor for IL-15 responsiveness, showed robust 9.19-fold upregulation (p<0.05), while NKG2D increased 8.59-fold (p<0.001) and NKp80 increased 4.91-fold (p<0.05). Conversely, early developmental markers CD127, CD7, and CD45RA were suppressed to 0.08, 0.09, and 0.02-fold of control levels, respectively (all p<0.001). Mechanistic analysis revealed that Metadichol enhances IL-15 signaling through the mTORC1→E4BP4→EOMES→CD122 positive feedback loop. Critically, despite NF-κB inhibition, Metadichol maintains IL-15 and IRF-1 regulation through alternative pathways including TLR-TRIF signaling, nuclear receptor activation (VDR, RARs, PPARs), sirtuin-mediated STAT modulation, and TP53-IRF-1 cross-regulation.Conclusions: Metadichol drives NK cell maturation through a novel push-pull mechanism that simultaneously accelerates developmental progression while suppressing progenitor phenotypes. The pronounced enhancement of CD122 expression amplifies IL-15 responsiveness through NF-κB-independent pathways, achieving immunomodulation that promotes NK cell cytotoxic capacity without excessive inflammation. These findings establish Metadichol as a promising agent for NK cell-based cancer immunotherapy and infectious disease treatment, offering a unique multi-pathway approach to enhancing innate immune function.