SB225002 Enhances Radiosensitivity in Cervical Cancer via Direct Neutrophil Inhibition and Tumor Cell Suppression.
Radiotherapy resistance is a major contributor to therapeutic failure in cervical cancer, largely due to the immunosuppressive tumor microenvironment (TME). Increasing clinical and experimental evidence underscores the role of neutrophils infiltration in reducing the efficacy of radiation therapy. Additionally, the CXCR2/CXCL signaling axis has been identified as a key regulator of neutrophils recruitment. Our study demonstrates that radiotherapy significantly enhances neutrophils infiltration by activating CXCR2-CXCL signaling and drives their polarization toward a pro-tumor N2-like phenotype through TGF-β signaling in cervical cancer. Further investigation revealed that CXCR2 antagonist SB225002 exerts a synergistic effect with radiotherapy and concurrent chemoradiotherapy in cervical cancer, primarily via inhibiting neutrophils infiltration and alleviating the immunosuppressive TME. Meanwhile, SB225002 exerts direct antitumor activity and enhances the radiosensitivity of cervical cancer cells by facilitating DNA double-strand breaks, promoting G2/M phase cell cycle arrest, and inducing apoptosis. In summary, our findings highlight neutrophils inhibition via CXCR2 antagonist as a promising therapeutic strategy to enhance cervical cancer responsiveness to radiotherapy.
