中性粒细胞是结肠肿瘤微环境中丰富的免疫细胞。研究表明，中性粒细胞被招募到结肠癌的缺氧病灶中。然而，缺氧信号对中性粒细胞功能的影响及其与结肠肿瘤发生的关系仍不清楚。为了解决这个问题，我们生成了由 MRP8Cre (HIF-1αΔNeu) 或 (HIF-2αΔNeu) 驱动的中性粒细胞缺氧 (HIF)-1α 或 HIF-2α 缺失的小鼠以及同窝对照小鼠。在偶氮甲烷 (AOM)/硫酸葡聚糖钠 (DSS) 结肠癌模型中，中性粒细胞-HIF-1α 的破坏不会导致体重、结肠长度、肿瘤大小、增殖或负担发生任何显着变化。然而，与同窝对照相比，中性粒细胞中 HIF-2α 的破坏导致体重略有增加，肿瘤数量显着减少，肿瘤大小和体积减小。对 HIF-2α 缺陷型中性粒细胞小鼠结肠组织的组织学分析显示，与对照小鼠相比，其增殖显着减少。此外，我们观察到中性粒细胞特异性 HIF-2α 缺陷小鼠的肿瘤组织和中性粒细胞中促炎细胞因子（例如 TNF-α 和 IL-1β）水平降低。重要的是，值得注意的是，与中性粒细胞中 HIF-2α 缺乏相关的肿瘤发生减少在已经建立的同基因肿瘤或 DSS 诱导的炎症模型中并不明显，表明 HIF-2α 在结肠肿瘤发生中具有潜在作用。总之，我们发现中性粒细胞特异性 HIF-2α 的丧失通过降低炎症介质的水平来减缓结肠肿瘤的生长和进展。

Neutrophils are abundant immune cells in the colon tumor microenvironment. Studies have shown that neutrophils are recruited into hypoxic foci in colon cancer. However, the impact of hypoxia signaling on neutrophil function and its involvement in colon tumorigenesis remain unclear. To address this, we generated mice with a deletion of hypoxia (HIF)-1α or HIF-2α in neutrophils driven by the MRP8Cre (HIF-1αΔNeu) or (HIF-2αΔNeu) and littermate controls. In an azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colon cancer, the disruption of neutrophils-HIF-1α did not result in any significant changes in body weight, colon length, tumor size, proliferation, or burden. However, the disruption of HIF-2α in neutrophils led to a slight increase in body weight, a significant decrease in the number of tumors, and a reduction in tumor size and volume compared to their littermate controls. Histological analysis of colon tissue from mice with HIF-2α-deficient neutrophils revealed notable reductions in proliferation as compared to control mice. Additionally, we observed reduced levels of pro-inflammatory cytokines, such as TNF-α and IL-1β, in neutrophil-specific HIF-2α deficient mice in both the tumor tissue as well as the neutrophils. Importantly, it is worth noting that the reduced tumorigenesis associated with HIF-2α deficiency in neutrophils was not evident in already established syngeneic tumors or a DSS-induced inflammation model, indicating a potential role of HIF-2α specifically in colon tumorigenesis. In conclusion, we found that the loss of neutrophil-specific HIF-2α slows colon tumor growth and progression by reducing the levels of inflammatory mediators.