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

Julian Chua1, Arshdeep Kaur2, Fynnis Mitchell1

  • 1Department of Biological Sciences, University of Calgary, Calgary, AB, Canada; The Riddell Centre for Cancer Immunotherapy, Arnie Charbonneau Cancer Institute, Calgary, AB, Canada.

Cell Reports. Medicine
|May 7, 2026
PubMed

Insights

Researchers discovered a specific cancer cell type in colorectal cancer (CRC) that hinders immunotherapy. Targeting these WNT/β-catenin inhibitory cancer cells (WICCs) and NOTUM could improve treatment effectiveness for MSS CRC patients.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Immunotherapy is largely ineffective in microsatellite stable (MSS) colorectal cancer (CRC).
  • Intratumoral heterogeneity complicates the identification of tumor-intrinsic immune resistance mechanisms.
  • Understanding these mechanisms is crucial for developing effective CRC treatments.

Purpose of the Study:

  • To identify novel tumor-intrinsic programs driving immune resistance in MSS CRC.
  • To characterize a specific cancer cell population associated with immune evasion.
  • To evaluate the WICC-NOTUM axis as a potential therapeutic target for CRC immunotherapy.

Main Methods:

  • Analysis of advanced-stage MSS CRC tumors and patient-derived tumoroids.
  • Identification and characterization of a novel cancer cell population (WICCs).
  • Assessment of WICC enrichment, NOTUM expression, and CD8+ T cell infiltration.
  • Functional studies involving selective WICC ablation and NOTUM knockout.

Main Results:

  • A distinct cancer cell population, WNT/β-catenin inhibitory cancer cells (WICCs), was identified in advanced MSS CRC.
  • WICCs exhibit stem-like features and aberrantly activate a WNT-inhibitory program with high NOTUM expression.
  • WICCs are enriched in immune-excluded tumors, correlating with reduced CD8+ T cell infiltration.
  • Selective WICC ablation or NOTUM knockout enhanced CD8+ T cell-mediated cytotoxicity.

Conclusions:

  • WICCs represent a tumor-intrinsic mechanism of immune evasion in MSS CRC.
  • The WICC-NOTUM axis is a tractable therapeutic target to overcome immunotherapy resistance in CRC.
  • Targeting WICCs and NOTUM may enhance the efficacy of immunotherapy in MSS CRC patients.
Keywords:
CD8(+) T cellsNOTUMWNT signalingcancer-stem-like cellscolorectal cancerimmunosuppressionimmunotherapymicrosatellite stablesingle-cell genomicstumor microenvironment

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