ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicDecoding Key Regulators in Cancer Immunotherapy and Chemotherapy: Integrating Single-Cell Technologies and Machine LearningView all 8 articles
NOTCH3 Attenuates Cytotoxicity via RBPJ-dependent PVR upregulation to Influence Immunotherapy Outcomes in Colorectal Cancer
Provisionally accepted
- 1Henan Cancer Hospital/Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
- 2Henan Provincial People's Hospital, Zhengzhou, China
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Colorectal cancer (CRC), a leading cause of cancer-related mortality, currently lacks reliable predictive biomarkers and validated therapeutic targets, particularly for predicting responses to immunotherapy. This study elucidates the role of NOTCH3—a member of the NOTCH signaling family—in pan-cancer and CRC progression, immune modulation, and therapeutic efficacy. Multi-omics analysis of TCGA datasets revealed widespread NOTCH3 alterations—including mutations, copy number variations, and epigenetic changes—across multiple malignancies. We found that elevated NOTCH3 expression in CRC was significantly correlated with poor survival outcomes. Notably, NOTCH3 mutations were associated with increased immune infiltration of specific CD8 ⁺ T cells and macrophages, whereas high NOTCH3 expression fostered an immunosuppressive microenvironment mediated by activating PVR expression, thereby suppressing CD8 ⁺ T cell cytotoxicity. Mechanistically, NOTCH3 transcriptionally upregulates PVR through RBPJ binding, a process that is abrogated by NOTCH3 mutations. In vitro and in vivo studies demonstrated that NOTCH3 depletion or mutation sensitizes CRC cells to anti – PD-L1 therapy and extends survival. Clinical validation across immunotherapy-treated CRC and pan-cancer cohorts confirmed that NOTCH3 mutation or low expression independently predicts improved prognosis. Collectively, our results identify NOTCH3 as a pivotal regulator of immune evasion in CRC and a promising predictive biomarker for immunotherapy outcomes, suggesting new therapeutic target for CRC patients.
Keywords: CRC, Immunotherapy, Mutation, Notch3, PVR, RBPJ
Received: 07 Nov 2025; Accepted: 14 Jan 2026.
Copyright: © 2026 Ma, Xu, Ma, Ke, Liu and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ying Liu
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