A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2026-05-06 DOI:10.1016/j.xcrm.2026.102776

Julian Chua, Arshdeep Kaur, Fynnis Mitchell, Anneke Korver, Parnika Sakthivel, Elleine Allapitan, Mahdin Uddin, Areeba Maqsood, Naomi Chege, Aralia Leon-Coria, Constance A M Finney, Oliver F Bathe, Parham Minoo, Arshad Ayyaz

{"title":"A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer.","authors":"Julian Chua, Arshdeep Kaur, Fynnis Mitchell, Anneke Korver, Parnika Sakthivel, Elleine Allapitan, Mahdin Uddin, Areeba Maqsood, Naomi Chege, Aralia Leon-Coria, Constance A M Finney, Oliver F Bathe, Parham Minoo, Arshad Ayyaz","doi":"10.1016/j.xcrm.2026.102776","DOIUrl":null,"url":null,"abstract":"Immunotherapy remains largely ineffective in colorectal cancer (CRC), particularly in microsatellite stable (MSS) tumors, which represent the majority of cases. However, the complexity of intratumoral heterogeneity has made it difficult to define tumor-intrinsic programs that drive immune resistance. Here, we identify a cancer cell population that emerges predominantly in advanced-stage MSS CRCs. These cells exhibit stem-like features but aberrantly activate a WNT-inhibitory transcriptional program marked by high NOTUM expression. We term these cells WNT/β-catenin inhibitory cancer cells (WICCs). WICCs are enriched in immune-excluded tumors, correlate with reduced CD8+ T cell infiltration, and are induced in both primary human CRC tumors and patient-derived tumoroids. Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8+ T-cell-mediated cytotoxicity, uncovering a tumor-intrinsic mechanism of immune evasion and nominating the WICC-NOTUM axis as a selective and tractable therapeutic target to overcome immunotherapy resistance in CRC.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102776"},"PeriodicalIF":10.6000,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Reports Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xcrm.2026.102776","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Immunotherapy remains largely ineffective in colorectal cancer (CRC), particularly in microsatellite stable (MSS) tumors, which represent the majority of cases. However, the complexity of intratumoral heterogeneity has made it difficult to define tumor-intrinsic programs that drive immune resistance. Here, we identify a cancer cell population that emerges predominantly in advanced-stage MSS CRCs. These cells exhibit stem-like features but aberrantly activate a WNT-inhibitory transcriptional program marked by high NOTUM expression. We term these cells WNT/β-catenin inhibitory cancer cells (WICCs). WICCs are enriched in immune-excluded tumors, correlate with reduced CD8⁺ T cell infiltration, and are induced in both primary human CRC tumors and patient-derived tumoroids. Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8⁺ T-cell-mediated cytotoxicity, uncovering a tumor-intrinsic mechanism of immune evasion and nominating the WICC-NOTUM axis as a selective and tractable therapeutic target to overcome immunotherapy resistance in CRC.

查看原文本刊更多论文

肿瘤固有的wnt抑制NOTUM程序驱动微卫星稳定型结直肠癌的免疫抵抗。

免疫治疗在结直肠癌（CRC）中仍然基本上无效，特别是在微卫星稳定（MSS）肿瘤中，这代表了大多数病例。然而，肿瘤内异质性的复杂性使得很难确定驱动免疫抵抗的肿瘤内在程序。在这里，我们确定了一个主要出现在晚期MSS crc中的癌细胞群。这些细胞表现出干细胞样的特征，但异常地激活了以高NOTUM表达为标志的wnt抑制转录程序。我们称这些细胞为WNT/β-连环蛋白抑制性癌细胞（WICCs）。WICCs在免疫排斥肿瘤中富集，与CD8+ T细胞浸润减少相关，并且在原发性人类CRC肿瘤和患者源性类肿瘤中均可诱导。选择性消融WICCs或基因敲除NOTUM可增强CD8+ t细胞介导的细胞毒性，揭示了肿瘤固有的免疫逃避机制，并将WICC-NOTUM轴作为克服CRC免疫治疗耐药的选择性和可处理的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.