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

Sep 22, 2026

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Advanced microsatellite stable colorectal cancers are difficult to treat due to immune exclusion and intratumoral heterogeneity. The study identifies NOTUM-high, WNT-inhibitory cancer cells (WICCs) enriched in advanced MSS tumors, showing stem-like features alongside aberrant WNT inhibitory transcriptional activity. WICCs correlate with reduced CD8+ T-cell infiltration and an immunologically cold microenvironment. Targeted WICC ablation and NOTUM knockout restore antitumor cytotoxicity and enhance tumor clearance, positioning the WICC-NOTUM axis as a tractable therapeutic target.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages26

Reading Time1 h 6 min

AccessFree to download

Summary

Highlights

WICCs in advanced MSS CRC

Links to immune exclusion

Therapeutic targeting via WICC ablation and NOTUM knockout

Introduction

CSCs and treatment resistance

Immunotherapy limits in MSS CRC

Main findings

Article A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer Graphical abstract Authors Julian Chua, Arshdeep Kaur, Fynnis Mitchell, ..., Oliver F. Bathe, Parham Minoo, Arshad Ayyaz Correspondence arshad.ayyaz@ucalgary.ca In brief Advanced microsatellite stable colorectal cancers are particularly difficult to treat due to immune exclusion. Chua et al. identify an NOTUM-high, WNT-inhibitory cancer cell (WICC) state enriched in these tumors that drives reduced CD8+ T cell infiltration. Disruption of the WICCNOTUM axis restores antitumor immunity and enhances tumor clearance. Highlights • scRNA-seq identifies NOTUM+ Wnt/βcatenin inhibitory cancer cells (WICCs) in advanced MSS CRC • WICCs are associated with immune exclusion • WICC ablation in tumoroids induces T-cell-mediated tumor killing • NOTUM knockout promotes tumor clearance with adoptive cell therapy Chua et al., 2026, Cell Reports Medicine 7, 102776 May 19, 2026 © 2026 The Author(s) . Published by Elsevier Inc. [https://doi.org/10.1016/j.xcrm.2026.102776](https://doi.org/10.1016/j.xcrm.2026.102776) ll ll OPEN ACCESS Article A tumor-intrinsic WNT-inhibitory NOTUM program drives immune resistance in microsatellite stable colorectal cancer Julian Chua,1,2 Arshdeep Kaur,1 Fynnis Mitchell,1,2 Anneke Korver,1,2 Parnika Sakthivel,1 Elleine Allapitan,3 Mahdin Uddin,1 Areeba Maqsood,1 Naomi Chege,1 Aralia Leon-Coria,1 Constance A. M. Finney,1 Oliver F. Bathe,3,4 Parham Minoo,5 and Arshad Ayyaz1,2,6,7,8,* 1Department of Biological Sciences, University of Calgary, Calgary, AB, Canada 2The Riddell Centre for Cancer Immunotherapy, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada 3Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 4Department of Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 5Department of Pathology, Cumming School of Medicine, and Alberta Precision Laboratories, University of Calgary, Calgary, AB, Canada 6The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Calgary, AB, Canada 7Alberta Children’s Hospital Research Institute, Calgary, AB, Canada 8Lead contact *Correspondence: arshad.ayyaz@ucalgary.ca [https://doi.org/10.1016/j.xcrm.2026.102776](https://doi.org/10.1016/j.xcrm.2026.102776) SUMMARY 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 immuneexcluded 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. INTRODUCTION Colorectal cancer (CRC) remains a leading cause of cancerrelated mortality worldwide.1 ,2 In particular, cases with advanced disease frequently fail to achieve long-term tumor control.3 ,4 A major barrier to successful treatment is the presence of cancerstem-like cells (CSCs), which survive therapies, reinitiate tumor growth, and drive metastatic progression.5–8 Thus, resistance to conventional chemoradiation therapies is generally linked to CSC programs.9–11 Recent studies have demonstrated that

FAQs

What problem does the study address in microsatellite stable colorectal cancer?

The study addresses the difficulty of treating advanced microsatellite stable (MSS) colorectal cancer due to immune exclusion and immune resistance. It highlights that intratumoral heterogeneity makes tumor-intrinsic immune evasive programs hard to define.

What are WICCs and how are they characterized?

WICCs are WNT/β-catenin inhibitory cancer cells marked by high NOTUM expression. They emerge predominantly in advanced-stage MSS CRC and show stem-like features together with a WNT-inhibitory transcriptional program.

How does targeting WICCs or NOTUM affect antitumor immunity?

Selective ablation of WICCs or genetic knockout of NOTUM enhances CD8+ T-cell-mediated cytotoxicity. This restores antitumor immunity and increases tumor clearance, supporting the WICC-NOTUM axis as a therapeutic target.

Sep 22, 2026

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