Neutrophil-intrinsic Vgll4 constrains tumorigenesis by preventing a STAT3/STAT5-driven immunosuppressive switch.

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.