Translational Insights into Interferon Alpha's Effects on Immunomolecular Dynamics in Philadelphia-Negative Myeloproliferative Neoplasms.

Background/Objectives: Interferon alpha (IFNα) remains a cornerstone in the management of Philadelphia-negative myeloproliferative neoplasms (Ph-neg MPNs), yet its immunomolecular impact over time is not fully elucidated. The aim of the study was to explore how IFNα therapy dynamically reshapes immune and gene profiles in Ph-neg MPNs and assess their potential as treatment-related biomarkers. Methods: This single-center, prospective, observational study included a translational substudy conducted within a previously established clinical cohort of 44 IFNα-treated patients, selecting a representative subset of 18 individuals stratified by treatment duration. Cytokine profiling (ELISA) and gene expression (RT-qPCR) analysis were performed using plasma and peripheral blood mononuclear cells (PBMCs), respectively. Results: Patients with prolonged exposure showed reduced pro-inflammatory cytokines and downregulation of inflammatory-signalling STAT1/STAT3 expression. In contrast, those with intermediate exposure exhibited transient TH2/regulatory cytokine peaks and upregulation of immunomodulatory genes such as CXCL10, SOCS3, and TNFAIP3. Spearman correlations revealed functional associations between cytokine and gene expression patterns including notable links such as STAT1-IL-13 and MYB-IL-13. Conclusions: These results describe a sequential immune reprogramming driven by IFNα, supporting the development of dynamic immunomolecular biomarkers of response in Ph-neg MPNs.