Colorectal cancer (CRC) is a highly malignant tumor with hypoxia being a crucial feature during its progression. This study utilized multiple independent CRC cohorts for bioinformatics analysis and in vitro experiments to investigate the role of hypoxia‐related subgroups in CRC. Machine learning was employed to construct risk features associated with this subgroup and further explore its therapeutic value in CRC. The study identified the GPNMB+ Macrophage (GPNMB+ Macr) subgroup as most relevant to hypoxia. GPNMB+ Macr showed significantly higher infiltration in tumor tissues compared to non‐tumor tissues, increasing with CRC stage. High infiltration of GPNMB+ Macr was associated with poor prognosis in terms of overall and recurrence‐free survival in CRC patients. GPNMB+ Macrophages exhibit M2‐like characteristics and have the ability to promote 5‐FU resistance, proliferation, and metastasis of CRC cells. The study developed the Hypoxia‐Related Macrophage Risk Score (HMRS), which not only served as an independent prognostic factor for CRC patients but also demonstrated robust prognostic performance compared to 84 previously published prognostic features. Patients with low HMRS were sensitive to fluorouracil, oxaliplatin (FOLFOX), and anti‐PD‐1 immunotherapy, while those with high HMRS showed resistance. Additionally, HMRS was identified as an independent prognostic factor in other digestive tract tumors (hepatocellular carcinoma, pancreatic cancer, esophageal cancer, and gastric cancer), indicating potential extrapolation to other tumor types. In conclusion, GPNMB+ Macr promotes the malignant progression of CRC, and HMRS serves as a powerful predictive tool for prognosis, chemotherapy, and immunotherapy in CRC patients, aiding in improving the quality of survival.

中文翻译：

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缺氧相关 GPNMB+ 巨噬细胞促进结直肠癌恶性进展及其相关风险特征是治疗结直肠癌患者的有力预测工具


结直肠癌 （CRC） 是一种高度恶性的肿瘤，缺氧是其进展过程中的关键特征。本研究利用多个独立的 CRC 队列进行生物信息学分析和体外实验，以研究缺氧相关亚组在 CRC 中的作用。采用机器学习构建与该亚组相关的风险特征，并进一步探索其在 CRC 中的治疗价值。该研究确定 GPNMB+ 巨噬细胞 （GPNMB+ Macr） 亚组与缺氧最相关。与非肿瘤组织相比，GPNMB+ Macr 在肿瘤组织中的浸润率显著升高，随着 CRC 分期的增加而增加。GPNMB+ Macr 的高浸润与 CRC 患者总生存期和无复发生存期的不良预后相关。GPNMB+ 巨噬细胞表现出 M2 样特征，具有促进 CRC 细胞 5-FU 耐药、增殖和转移的能力。该研究开发了缺氧相关巨噬细胞风险评分 （HMRS），该评分不仅作为 CRC 患者的独立预后因素，而且与先前发表的 84 个预后特征相比，该评分还显示出稳健的预后表现。低 HMRS 患者对氟尿嘧啶、奥沙利铂 （FOLFOX） 和抗 PD-1 免疫治疗敏感，而高 HMRS 患者表现出耐药。此外，HMRS 被确定为其他消化道肿瘤 （肝细胞癌、胰腺癌、食管癌和胃癌） 的独立预后因素，表明可能外推到其他肿瘤类型。综上所述，GPNMB+ Macr 促进 CRC 的恶性进展，HMRS 是 CRC 患者预后、化疗和免疫治疗的有力预测工具，有助于提高生存质量。