ABCG2-autophagy regulatory axis in cancer stem cells - implication in cancer metastasis, recurrence and chemotherapy resistance

Sep 22, 2026

Cancer stem cells (CSCs) drive tumor initiation, metastasis, recurrence, and therapeutic resistance, making them central targets for improved oncology outcomes. ATP-binding cassette transporter G2 (ABCG2) functions as a CSC marker by regulating CSC traits and promoting drug efflux, which supports chemoresistance. Autophagy, a stress-adaptive catabolic pathway, enhances CSC survival. This review synthesizes evidence for coordinated regulation between ABCG2 and autophagy, highlighting pathways and transcription factors and evaluating pharmacological and combination strategies to disrupt the axis and reduce resistance, metastasis, and recurrence.

LanguageEnglish

CategoryResearch & Report

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Pages27

Reading Time1 h 8 min

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Abstract

Introduction

Zalpoor et al. Cell Communication and Signaling (2026) 24:332 [https://doi.org/10.1186/s12964-026-02853-9](https://doi.org/10.1186/s12964-026-02853-9) Cell Communication and Signaling REVIEW Open Access ABCG2-autophagy regulatory axis in cancer stem cells: implication in cancer metastasis, recurrence and chemotherapy resistance Hamidreza Zalpoor1,2, JunYaoTeow3, Saeid Ferdousmakan4†, Nafiseh Golestani5†, Mohsen Nabi-afjadi5* and Thamil Selvee Ramasamy3* Abstract Cancer stem cells (CSCs) play a key role in tumor initiation, metastasis, recurrence, and therapeutic resistance. ATPbinding cassette (ABC) transporter G2 (ABCG2) is a stem cell marker that not only regulates CSC properties but also by drug efflux contributes to chemoresistance. Autophagy is a catabolic process that supports CSC survival under stress. Emerging evidence suggests a regulatory relationship between ABCG2 and autophagy in maintaining the CSC phenotype. This review discusses the potential associations between different signaling pathways and transcription factors including hypoxia inducible factor-1 alpha (HIF-1α), nuclear factor erythroid 2–related factor 2 (Nrf2), estrogen receptor alpha (ERα), CCAAT/enhancer-binding protein β (C/EBPβ), NF-κB, protein kinase R-like ER kinase (PERK), peroxisome proliferator-activated receptor gamma (PPARγ), and Notch and induction of autophagy and ABCG2 expression in CSCs. Evidence is presented for how ABCG2-induced autophagy impacts metastasis, recurrence and drug resistance. Pharmacological strategies targeting ABCG2 and autophagy are examined for overcoming drug resistance. Combination therapies disrupting the ABCG2-autophagy axis may provide a novel approach for eliminating CSCs and improving treatment outcomes to reduce risk of drug resistance, tumor metastasis and recurrence. Future studies on elucidating the complex regulatory networks between these pathways offer opportunities to enhance current therapeutic approaches for controlling cancer progression. Keywords Cancer stem cell, Autophagy, ABCG2, Metastasis, Recurrence, Drug resistance †Saeid Ferdousmakan and Nafiseh Golestani contributed equally to this work. *Correspondence: Mohsen Nabi-afjadi [mohsennabi66@gmail.com](mohsennabi66@gmail.com)[ ](mohsennabi66@gmail.com)Thamil Selvee Ramasamy [selvee@ummc.edu. my](selvee@ummc.edu. my) 1Department of Biotechnology, Institute of Natural and Applied Sciences,Çukurova University, Balcalı, Adana, Turkey 2Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran 3Stem Cell Biology Laboratory, Department of Molecular Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia 4Department of Pharmacy Practice, Nargund College of Pharmacy, Bangalore 560085, India 5Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran © 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/licenses/by-nc-nd/4.0/](vecommons.

FAQs

What roles do cancer stem cells play in cancer progression?

Cancer stem cells (CSCs) are linked to tumor initiation, metastasis, recurrence, and therapeutic resistance, contributing to poor prognosis and treatment failure.

How does ABCG2 relate to chemoresistance in CSCs?

ABCG2 regulates CSC properties and supports chemoresistance through drug efflux, helping CSCs withstand chemotherapy.

Why is autophagy important for CSC survival and treatment response?

Autophagy recycles intracellular components to generate energy and maintain homeostasis, enabling CSCs to survive under metabolic and stress conditions and contributing to therapy resistance.

Sep 22, 2026

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