Decoding Triphenotypic Neutrophils in Cervical Cancer Evolution and Targeting SPP1+/GBP1+/ELOVL5+ Tumor‐Associated Neutrophils to Sensitize Immunotherapy

Enhancing cervical cancer (CC) immunotherapy requires deciphering the heterogeneous tumor immune microenvironment (TIME), particularly neutrophil phenotypic dynamics. Here, 1) we collected 543 CC cases to find that patients with elevated neutrophil levels have a higher incidence of high-risk pathological factors. 2) Three tissue-specific neutrophils stages are revealed across cervical carcinogenesis. Specifically, in the normal stage, normal-associated neutrophils (NANs) served as defenders to predominantly exert immune surveillance. In the HSIL stage, precancerous-associated neutrophils (PANs) served as agitators to boost inflammation-cancer transition. 3) In the CC stage, tumor cells and tumor-associated neutrophils (TANs) engage in a detrimental "positive feedback loop" that drives CC aggressiveness. Specifically, tumor cells educated TANs to overexpress SPP1, GBP1, and ELOVL5, which subsequently activated three key mechanisms: promoting angiogenesis (SPP1-NF-κB-HIF/VEGF), immunosuppression (GBP1-NF-κB-PD-L1), and dysregulated oxidative lipid metabolism (ELOVL5-NF-κB), leading to poor prognosis. 4) Finally, to explore the therapeutic value of TANs, we performed in vivo experiments, demonstrating that the combination of anti-Ly6G and anti-PD1 therapy resulted in improved anti-tumor efficacy compared with anti-PD1 monotherapy for CC. In conclusion, the study innovatively elucidated the three tissue-specific neutrophils stages in the progression of "normal-HSIL-CC", providing novel insights into TANs as potential targets for improving CC immunotherapeutic efficacy.