Authors
Lin Shao, Jingwu Yue, Shilong Wang, Ruixian Yu, Shuting Cheng, Pingping Nie, Xiaoya Jiang, Yi Han, Wenjia Wang, Yan Meng, Moubin Lin, Miao He, Jianfeng Chen, Zhaocai Zhou, Shi Jiao
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 34. Pages e2606983123. Aug 25, 2026. Epub Aug 19, 2026.
Abstract
Neutrophils display profound functional plasticity within the tumor microenvironment (TME), a key determinant of cancer progression; however, the intrinsic mechanisms safeguarding their antitumor identity remain elusive. Here, we identify the Hippo pathway component Vgll4 as a pivotal guardian of neutrophil functional fate in the TME. While dispensable for homeostatic granulopoiesis, Vgll4 in neutrophils is crucial for restraining tumor growth. Neutrophil-specific ablation of Vgll4 triggers a phenotypic shift toward an immunosuppressive state, accelerating tumor progression. Mechanistically, Vgll4 binds STAT3 and STAT5 in a JAK-dependent manner; loss of Vgll4 reduces SOCS3 expression, a negative regulator of STAT3, thereby unleashing STAT3 hyperactivation while suppressing STAT5, leading to transcriptional reprogramming that establishes an immunosuppressive profile. This regulatory axis operates specifically in tumor-associated neutrophils, as Vgll4 is dispensable for steady-state development but essential within the TME. Consequently, Vgll4-deficient neutrophils remodel the TME by promoting regulatory T cell (Treg) differentiation and impairing CD8+ T cell effector function. Our findings unveil a noncanonical role for Vgll4 in innate immune regulation and establish the Vgll4-STAT3/STAT5 axis as a crucial checkpoint in neutrophil polarization, presenting a therapeutic target for cancer immunotherapy.
PMID:
42616777
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.
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