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Resistance of Colorectal Cancer Stem Cells to Modern Therapies: A Systematic Review

Sarzhan Rustemov1, Alina Kuandyk2, Arailym Bertleuova2

  • 1Department of Medicine, Nazarbayev University School of Medicine, Kerey-Zhanibek Khandar 5/1, Astana 010000, Kazakhstan.

International Journal of Molecular Sciences
|July 28, 2026
PubMed

Insights

Colorectal cancer stem cells (CRC-SCs) resist modern therapies through adaptive signaling, epigenetic changes, and tumor microenvironment interactions. Combination treatments targeting these mechanisms show promise in preclinical studies.

Area of Science:

  • Oncology
  • Cancer Stem Cell Biology
  • Molecular Mechanisms of Cancer

Background:

  • Colorectal cancer stem cells (CRC-SCs) are key drivers of treatment resistance, recurrence, and progression.
  • Current understanding of CRC-SC resistance mechanisms is fragmented despite therapeutic advances.

Purpose of the Study:

  • To systematically review and synthesize preclinical evidence on molecular mechanisms of CRC-SC resistance to contemporary anticancer therapies.
  • To consolidate fragmented knowledge for a comprehensive understanding of CRC-SC evasion strategies.

Main Methods:

  • Systematic literature search of major databases (PubMed, Scopus, Web of Science, Cochrane) for studies published 2015-2025.
  • Inclusion of studies investigating molecular mechanisms of CRC-SC resistance to chemotherapy, targeted therapy, and immunotherapy.
  • Risk of bias assessment using QUIN (in vitro) and SYRCLE (in vivo) tools.

Main Results:

  • Twenty-six studies met the inclusion criteria, revealing interconnected resistance mechanisms.
  • Key mechanisms include adaptive signaling, epigenetic reprogramming, enhanced DNA repair, and tumor microenvironment interactions.
  • Combination therapies targeting these pathways demonstrated potential to reduce stemness and improve sensitivity.

Conclusions:

  • CRC-SC resistance is multifactorial, involving both intrinsic and extrinsic cellular processes.
  • Preclinical evidence supports the evaluation of combination strategies to overcome CRC-SC-mediated therapeutic resistance.
  • Further translational research is warranted to validate these combination approaches in clinical settings.
Keywords:
DNA damage response (DDR)cancer stem cells (CSCs)colorectal cancercolorectal cancer stem cells (CRC-SCs)drug resistanceepigenetic reprogrammingsignaling plasticitytherapeutic resistancetumor microenvironment (TME)

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