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Translational insights and clinical challenges of targeting cancer stem cells

Ahmed, Mehreen LU ; Al-Haidari, Amr LU ; Agarwal, Shruti LU ; Sun, Jianmin LU ; Hammarlund, Emma U LU orcid ; Rönnstrand, Lars LU orcid ; Pienta, Kenneth J LU ; Tatli, Özge LU and Kazi, Julhash U LU orcid (2026) In Signal Transduction and Targeted Therapy 11. p.1-37
Abstract

Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as... (More)

Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.

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Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Neoplastic Stem Cells/pathology, Neoplasms/pathology, Animals, Tumor Microenvironment/genetics, Translational Research, Biomedical
in
Signal Transduction and Targeted Therapy
volume
11
article number
323
pages
1 - 37
publisher
Springer Nature
external identifiers
  • scopus:105047164222
  • pmid:42586960
ISSN
2059-3635
DOI
10.1038/s41392-026-02887-y
language
English
LU publication?
yes
additional info
© 2026. The Author(s).
id
fe55f732-bc4d-4b17-b279-f8c2f22f7d6a
date added to LUP
2026-08-22 23:40:49
date last changed
2026-09-06 04:55:56
@article{fe55f732-bc4d-4b17-b279-f8c2f22f7d6a,
  abstract     = {{<p>Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.</p>}},
  author       = {{Ahmed, Mehreen and Al-Haidari, Amr and Agarwal, Shruti and Sun, Jianmin and Hammarlund, Emma U and Rönnstrand, Lars and Pienta, Kenneth J and Tatli, Özge and Kazi, Julhash U}},
  issn         = {{2059-3635}},
  keywords     = {{Humans; Neoplastic Stem Cells/pathology; Neoplasms/pathology; Animals; Tumor Microenvironment/genetics; Translational Research, Biomedical}},
  language     = {{eng}},
  month        = {{08}},
  pages        = {{1--37}},
  publisher    = {{Springer Nature}},
  series       = {{Signal Transduction and Targeted Therapy}},
  title        = {{Translational insights and clinical challenges of targeting cancer stem cells}},
  url          = {{http://dx.doi.org/10.1038/s41392-026-02887-y}},
  doi          = {{10.1038/s41392-026-02887-y}},
  volume       = {{11}},
  year         = {{2026}},
}