IFNα2b modulates anti-tumor immune responses involving STAT3-associated dendritic cell dysfunction in JAK2v617f-positive myeloproliferative neoplasms.

AIMS: To define JAK2v617f-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in JAK2v617f-positive myeloproliferative neoplasms.

METHODS

Integrated flow cytometry and single-cell RNA sequencing profiled immune landscapes and signaling pathways, while functional assays assessed dendritic cell differentiation, T cell activation, and IFNα2b-mediated immune restoration.

RESULTS

JAK2v617f was associated with increased STAT3 activation in myeloid cells, accompanied by elevated expression of immunosuppressive mediators such as FGL2, impaired monocyte-to-DC differentiation, reduced cDC1/cDC2 subsets, and diminished T cell activation, consistent with an immunosuppressive immune landscape. IFNα2b treatment was associated with attenuation of STAT3/FGL2 signaling and partial restoration of DC-mediated T cell priming, with more pronounced immunomodulatory effects observed in JAK2v617f-positive myeloproliferative neoplasms compared with other subtypes.

CONCLUSIONS

Our findings indicate that JAK2v617f is associated with STAT3-dependent dendritic cell dysfunction that contributes to an immunosuppressive milieu. IFNα2b modulates this pathway and partially restores DC-T cell interactions, highlighting its potential as an immunomodulatory strategy in JAK2v617f-positive myeloproliferative neoplasms.