由于免疫抑制性肿瘤微环境（TME），免疫疗法对结直肠癌（CRC）的反应率有限。结合转录组测序、临床标本和功能实验，我们鉴定了一组独特的 CAF 亚群 (COX4I2)，其线粒体呼吸受到抑制，糖酵解增强。通过生物信息学预测和荧光素酶报告基因检测，我们确定EBF1可以上游调节COX4I2转录。 COX4I2 CAF 在功能和表型上类似于肌成纤维细胞，对于纤维化 TME 的形成很重要，并且能够激活巨噬细胞的 M2 表型。体外实验表明，COX4I2 CAF 通过阻断 CD8 T 细胞浸润并诱导 CD8 T 细胞功能障碍来促进免疫抑制性 TME。使用多个独立队列，我们​​还发现 CRC 患者的免疫治疗反应率与其肿瘤中 COX4I2 表达之间存在很强的相关性。我们的结果确定了一个以 EBF1-COX4I2 轴激活为特征的 CAF 亚群，这组 CAF 可以作为改善癌症免疫治疗结果的目标。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Immunotherapy has limited response rates in colorectal cancer (CRC) due to an immunosuppressive tumor microenvironment (TME). Combining transcriptome sequencing, clinical specimens, and functional experiments, we identified a unique group of CAF subpopulations (COX4I2 + ) with inhibited mitochondrial respiration and enhanced glycolysis. Through bioinformatics predictions and luciferase reporter assays, we determined that EBF1 can upstreamly regulate COX4I2 transcription. COX4I2 + CAFs functionally and phenotypically resemble myofibroblasts, are important for the formation of the fibrotic TME, and are capable of activating the M2 phenotype of macrophages. In vitro experiments demonstrated that COX4I2 + CAFs promote immunosuppressive TME by blocking CD8 + T cell infiltration and inducing CD8 + T cell dysfunction. Using multiple independent cohorts, we also found a strong correlation between the immunotherapy response rate of CRC patients and COX4I2 expression in their tumors. Our results identify a CAF subpopulation characterized by activation of the EBF1-COX4I2 axis, and this group of CAFs can be targeted to improve cancer immunotherapy outcomes.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.