Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials

Sep 22, 2026

Uploaded by Miles

Colorectal cancer (CRC) remains a major global health burden, as therapeutic resistance causes most treatment failures and cancer-related deaths. Cancer stem cells (CSCs) promote primary and acquired resistance through intrinsic drug tolerance and self-renewal. Core signaling cascades including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK, together with EMT, enhanced DNA repair, and PD-1/PD-L1 immune evasion, remodel the tumor microenvironment into a stemness-supportive immunosuppressive niche.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages22

Reading Time55 min

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Abstract

Molecular mechanisms of CSC-driven resistance

CSCs-directed therapeutic advances and combinations

Challenges and future directions

Zhou et al. Molecular Cancer (2026) 25:54 Molecular Cancer [https://doi.org/10.1186/s12943-025-02557-7](https://doi.org/10.1186/s12943-025-02557-7) REVIEW Open Access Cancer stem cell-driven drug resistance in colorectal carcinoma: molecular aspects and therapeutic potentials Minfeng Zhou1†, Huifang Niu2,3†, Dandan Cui1†, Menghao Xu1†, Jinxiao Li1, Guichen Huang1, Minquan Zhou4, Chutong Xiong1, Yunya Liu1, Xiaojuan Xu1*, Hongxing Zhang3*, Fengxia Liang5* and Rui Chen1* Abstract Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic drug tolerance and self-renewal capacity, drive both primary and acquired resistance. CSCs maintain drug tolerance through the activation of core signaling cascades, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ ERK pathways, as well as through epithelial–mesenchymal transition (EMT), enhanced DNA repair, and PD-1/ PD-L1-mediated immune evasion. These molecular alterations transform the tumor microenvironment (TME) into a stemness-supportive, immunosuppressive niche, thereby promoting tumor recurrence and metastasis. Recent advances in CSCs-directed therapy include monoclonal antibodies targeting stem cell surface antigens, small-molecule inhibitors that disrupt self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies aimed at reactivating anti-tumor immune surveillance. Emerging multi-drug regimens that combine CSCs-targeted agents with chemotherapy, pathway inhibitors, or immune checkpoint blockade exhibit synergistic efficacy by simultaneously disrupting multiple resistance mechanisms. Additionally, nanotechnologybased delivery systems further improve drug bioavailability and tumor specificity while reducing systemic toxicity. Despite notable progress, substantial challenges remain, including the pronounced heterogeneity of CSCs, activation of compensatory signaling pathways, and the lack of robust biomarkers for CSCs identification and therapeutic monitoring. Future research should prioritize integrative multi-omics approaches to delineate CSCsspecific vulnerabilities, the rational development of synergistic combination therapies, and the efficient clinical translation of CSCs-directed strategies. This review aims to describe the molecular mechanisms of CSCs-driven drug †Minfeng Zhou, Huifang Niu, Dandan Cui and Menghao Xu contributed equally the same in this article. *Correspondence: Xiaojuan Xu [xu_xiaojuan2009@163.com](xu_xiaojuan2009@163.com)[ ](xu_xiaojuan2009@163.com)Hongxing Zhang [zhxzj99@aliyun.com](zhxzj99@aliyun.com)[ ](zhxzj99@aliyun.com)Fengxia Liang [fxliang5@hotmail.com](fxliang5@hotmail.com)[ ](fxliang5@hotmail.com)Rui Chen [unioncr@163.com](unioncr@163.com) Full list of author information is available at the end of the article © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/li

FAQs

How do cancer stem cells drive drug resistance in colorectal carcinoma?

CSCs maintain intrinsic drug tolerance and self-renewal, enabling primary and acquired resistance. They sustain core signaling pathways and also support EMT, DNA repair, and immune evasion.

Which signaling pathways are highlighted as important for CSC-mediated resistance?

Key pathways include Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK. These molecular cascades contribute to maintaining stemness and resistance phenotypes.

What therapeutic approaches are discussed for targeting CSC-driven resistance?

The review highlights monoclonal antibodies against stem-cell surface antigens, small-molecule inhibitors of self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies to restore anti-tumor immune surveillance. It also emphasizes combination regimens and nanotechnology-based delivery systems.

Sep 22, 2026

Uploaded by Miles