Neutrophil-specific targeting of STAT3 impairs tumor progression via the expansion of cytotoxic CD8+ T cells

Neutrophils have emerged as key players in tumor progression, often associated with poor prognosis. Despite the ongoing efforts to target neutrophil functions in cancer, therapeutic success has been limited. In this study, we addressed the possibility of blocking STAT3 signaling in neutrophils as targeted therapeutic intervention in cancer. Conditional deletion of Stat3 in neutrophil-specific manner (Ly6GcreStat3fl/fl mice) significantly impaired tumor growth and metastasis in mice. Neutrophils isolated from these mice exhibited strong antitumoral phenotype, with increased MHCII, CD80/86 and ICAM-1 expression. Immune profiling of tumors and tumor-draining lymph nodes revealed a significant enrichment of CD8+ T cells (granzymeBhi, perforinhi and IFN-γhi) with strong cytotoxic activity. To further translate these findings to human settings, we blocked STAT3 signaling in patient neutrophils using a small molecule inhibitor LLL12 and assessed their effects on patient-derived cancer explants. In agreement with in vivo mouse data, we observed the expansion and activation of cytotoxic CD8+ T cells in such explants. To test the therapeutic applicability of STAT3 targeting, we utilized myeloid cell-selective STAT3 siRNA (CpG-STAT3ASO) to target neutrophils in vivo in tumor-bearing mice. Consistent with previous results, neutrophil-specific STAT3 knockdown impaired tumor growth and enhanced cytotoxic T cell activity in tumors and tumor-draining lymph nodes of treated mice. These findings highlight STAT3 signaling as a deleterious pathway supporting protumoral activity of neutrophils and suggest neutrophil-targeted STAT3 inhibition as a promising opportunity for cancer immunotherapy, providing novel insights in targeted therapeutic avenues.