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Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

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Review

Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review)

  • Authors:
    • Hanning Xu
    • Qunchao Si
    • Yongyao Song
    • Shengping Sun
    • Xianghong Wei
    • Hui Long
    • Xiaomei Wang
  • View Affiliations / Copyright

    Affiliations: Clinical Research Center of Gastroenterology Department, Tianyou Hospital, Affiliated to College of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430065, P.R. China, Hanchuan Center for Disease Control and Prevention, Hanchuan, Hubei 431699, P.R. China
  • Article Number: 18
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    Published online on: December 4, 2025
       https://doi.org/10.3892/ijo.2025.5831
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Abstract

Cancer stem cells (CSCs), a small subpopulation of cancer cells that exhibit stem‑like properties, possess the ability to differentiate and self‑renew. These capabilities enable CSCs to act as tumor‑initiating cells, driving tumorigenesis and proliferation, leading to major clinical challenges. Specifically, CSCs play a crucial role in metastasis, recurrence and drug resistance, thereby leading to complications in therapeutic responses. The plasticity of CSCs leads to heterogeneity, allowing them to adopt diverse phenotypes in response to intrinsic genetic factors or extrinsic environmental cues. This adaptability may serve as a mechanism for CSCs to thrive in the tumor microenvironment (TME) and promote tumor progression. The present article aimed to review the multifaceted nature of CSCs, examining their functional diversity, biomarkers and interactions with the TME. Through elucidating the mechanisms that underlie this heterogeneity, researchers aim to develop targeted therapeutic interventions against CSCs, thereby enhancing the efficacy of cancer treatments and improving patient outcomes.
View Figures

Figure 1

Schematic illustration of CSC
heterogeneity and its associated mechanisms in tumor progression.
Heterogeneity manifests via function multiplicity: i) Immune
evasive mimicry via MHC-I downregulation, PD-L1 upregulation or
viral-like IFN release attenuates the immune killing effects of T
cells and NK cells; ii) endothelial mimicry participates in
neovascularization; and iii) dormancy regulation through phenotypic
switching between differentiation and dormancy states facilitates
metastatic dissemination. Heterogeneity manifests via diverse CSC
biomarkers, including lipid raft-associated proteins (such as CD133
and CD47), ALDH enzymatic activity and mechanisms counteracting
replication stress. Heterogeneity arises from CSC-TME symbiotic
interactions, featuring: i) EMT, EV-mediated communication or
cancer-associated fibroblast-driven CSC niche maintenance; ii)
polarization of tumor-associated immune cells (such as TAM2 and
TAN2) that promote immune evasion; and iii) ECM remodeling, which
establishes pro-tumorigenic pH niches. Created using BioRender.
IFN, interferon; EMT, epithelial-mesenchymal transition; EV,
extracellular vesicle; PD-L1, programmed death-ligand 1; ALDH,
aldehyde dehydrogenase; TAM2, type-2 tumor-associated macrophage;
TAN2, type-2 tumor-associated neutrophils; ECM, extracellular
matrix; TME, the tumor microenvironment; MSC, mesenchymal stem
cells; CSC, cancer stem cell; CAF, cancer-associated fibroblast;
CTL, cytotoxic T cell; SIRPα, signal-regulatory protein α; MHC-I,
major histocompatibility class I; Hh, Hedgehog.

Figure 2

Current research advances in
CSC-targeted therapies based on endogenous biomarkers can be
achieved through multiple approaches: i) Direct CSC targeting via
receptor-ligand interaction-mediated conjugation or
carrier-encapsulated drug delivery systems; ii) precision targeting
through click chemistry-engineered novel surface markers; iii) CSC
eradication via DC-mediated presentation of CSC-specific antigens
to activate antigen-specific cellular immunity; and iv) direct CSC
attack using engineered CAR-T cell constructs. Created using
BioRender. CSC, cancer stem cell; CAR-T, chimeric antigen receptor
T; DC, dendritic cell; ATA, autologous tumor antigen; ALDH,
aldehyde dehydrogenase.
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Copy and paste a formatted citation
Spandidos Publications style
Xu H, Si Q, Song Y, Sun S, Wei X, Long H and Wang X: Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review). Int J Oncol 68: 18, 2026.
APA
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., & Wang, X. (2026). Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review). International Journal of Oncology, 68, 18. https://doi.org/10.3892/ijo.2025.5831
MLA
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., Wang, X."Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review)". International Journal of Oncology 68.2 (2026): 18.
Chicago
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., Wang, X."Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review)". International Journal of Oncology 68, no. 2 (2026): 18. https://doi.org/10.3892/ijo.2025.5831
Copy and paste a formatted citation
x
Spandidos Publications style
Xu H, Si Q, Song Y, Sun S, Wei X, Long H and Wang X: Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review). Int J Oncol 68: 18, 2026.
APA
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., & Wang, X. (2026). Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review). International Journal of Oncology, 68, 18. https://doi.org/10.3892/ijo.2025.5831
MLA
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., Wang, X."Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review)". International Journal of Oncology 68.2 (2026): 18.
Chicago
Xu, H., Si, Q., Song, Y., Sun, S., Wei, X., Long, H., Wang, X."Cancer stem cell heterogeneity‑inspired therapeutics for enhancing tumor treatment outcomes (Review)". International Journal of Oncology 68, no. 2 (2026): 18. https://doi.org/10.3892/ijo.2025.5831
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