Nature Communications · 15 authors, 10 centres
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The study investigates how Smad3 signaling in tumor-associated neutrophils (TANs) regulates their polarization between protumor N2 and antitumor N1 states in non-small cell lung cancer. The central finding is that Smad3 drives a protumor N2 state, while its deletion or inhibition promotes an antitumor N1 state, leading to enhanced tumor regression in preclinical models.
This study combines human NSCLC biopsy analysis with extensive preclinical mouse experiments to examine the role of Smad3 signaling in tumor-associated neutrophil (TAN) polarization. In human NSCLC, Smad3 activation in N2 TANs correlated negatively with N1 TANs and patient survival. In a mouse Lewis lung carcinoma model, Smad3-KO mice exhibited a switch from protumor N2 to antitumor N1 TANs, associated with enhanced neutrophil infiltration and tumor regression. Adoptive transfer of Smad3-KO neutrophils reproduced this protective effect, while neutrophil depletion abrogated it. Single-cell RNA sequencing revealed that Smad3 deficiency drives TAN maturation toward an N1 phenotype. Mechanistic studies identified Smad3 target genes related to cell fate determination. Pharmaceutical inhibition of Smad3 also promoted N1 polarization and suppressed tumor growth. The findings suggest Smad3 in neutrophils could be a therapeutic target for cancer immunotherapy.
