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 and are often associated with poor prognosis. Despite 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 a targeted therapeutic intervention in cancer. Conditional deletion of Stat3 in a neutrophil-specific manner (Ly6G^creStat3^fl/fl mice) significantly impaired tumor growth and metastasis in mice. Neutrophils isolated from these mice exhibited a strong antitumoral phenotype, with increased MHCII, CD80/86 and ICAM-1 expression. Immune profiling of tumors and tumor-draining lymph nodes of these mice revealed significant enrichment of CD8⁺ T cells (granzymeB^hi, perforin^hi and IFN-γ^hi) with strong cytotoxic activity. To further translate these findings to human settings, we blocked STAT3 signaling in cancer patient neutrophils via the small molecule inhibitor LLL12 and assessed its effects on patient-derived tumor explants. In agreement with the 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 antisense oligonucleotide (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 the tumors and tumor-draining lymph nodes of treated mice. These findings highlight STAT3 signaling as a deleterious pathway supporting the protumoral activity of neutrophils and suggest that neutrophil-targeted STAT3 inhibition is a promising opportunity for cancer immunotherapy, providing novel insights into targeted therapeutic avenues.