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Peer-reviewedCC BY-NC-NDSignal Transduction and Targeted Therapy

Tumor heterogeneity: development, mechanisms, and therapeutic implications

  • Jianhong Zhang1
  • Heng Li1
  • Shuo Ru2,3
  • Hui Feng1
  • Guo J4
  • Danlei Sun1
  • Tingxiu Xiang5
  • Daqian Xu6,7
  • Yang Luo8,9
9 affiliations
  1. 1Department of Laboratory Medicine, Chongqing Center for Clinical Laboratory, Chongqing Academy of Medical Sciences, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, China
  2. 2Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China
  3. 3Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
  4. 4Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
  5. 5Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing University Cancer Hospital, Chongqing, China. [email protected]
  6. 6Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou, China. [email protected]
  7. 7Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected]
  8. 8College of Life Science and Laboratory Medicine, Kunming Medical University, Kunming, China. [email protected]
  9. 9Department of Laboratory Medicine, Chongqing Center for Clinical Laboratory, Chongqing Academy of Medical Sciences, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, China. [email protected]
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Abstract

Tumor heterogeneity is a fundamental hallmark of cancer that drives progression, metastasis and therapeutic resistance. This diversity originates from persistent genomic instability, dynamic clonal evolution, and cancer stem cell plasticity, which are further amplified through complex crosstalk within the tumor microenvironment. While conventional therapies effectively eliminate certain tumor cell populations, residual resistant subclones frequently lead to disease relapse. Recent breakthroughs in single-cell multi-omics, spatial transcriptomics, and liquid biopsy now enable a comprehensive, multidimensional dissection of tumor heterogeneity across molecular, cellular, spatial, and temporal scales. These approaches reveal real-time dynamics of tumor evolution, providing new opportunities for therapeutic intervention. This review synthesizes key advances in understanding tumor heterogeneity: from its cellular origins and molecular mechanisms to its multidimensional manifestation in the tumor microenvironment and from metastatic heterogeneity to the fundamental causes of treatment resistance. We critically examine how these insights are informing novel therapeutic paradigms-including targeting clonal cooperative networks, modulating epigenetic plasticity and reprogramming metabolic adaptations. Finally, we outline future pathways toward precision medicine through the integration of multi-omics data and dynamic monitoring technologies. Ultimately, overcoming tumor heterogeneity necessitates reconceptualizing cancer not as a static collection of cells but as a dynamically evolving ecosystem.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026tumor,
  title = {{Tumor heterogeneity: development, mechanisms, and therapeutic implications}},
  author = {Jianhong Zhang and Heng Li and Shuo Ru and Hui Feng and Guo J and Danlei Sun and Tingxiu Xiang and Daqian Xu and Yang Luo},
  journal = {Signal Transduction and Targeted Therapy},
  year = {2026},
  month = jul,
  doi = {10.1038/s41392-026-02749-7},
  url = {https://doi.org/10.1038/s41392-026-02749-7},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Tumor heterogeneity: development, mechanisms, and therapeutic implications
AU  - Jianhong Zhang
AU  - Heng Li
AU  - Shuo Ru
AU  - Hui Feng
AU  - Guo J
AU  - Danlei Sun
AU  - Tingxiu Xiang
AU  - Daqian Xu
AU  - Yang Luo
PY  - 2026
DA  - 2026/07/12
JO  - Signal Transduction and Targeted Therapy
DO  - 10.1038/s41392-026-02749-7
UR  - https://doi.org/10.1038/s41392-026-02749-7
AB  - Tumor heterogeneity is a fundamental hallmark of cancer that drives progression, metastasis and therapeutic resistance. This diversity originates from persistent genomic instability, dynamic clonal evolution, and cancer stem cell plasticity, which are further amplified through complex crosstalk within the tumor microenvironment. While conventional therapies effectively eliminate certain tumor cell populations, residual resistant subclones frequently lead to disease relapse. Recent breakthroughs in single-cell multi-omics, spatial transcriptomics, and liquid biopsy now enable a comprehensive, multidimensional dissection of tumor heterogeneity across molecular, cellular, spatial, and temporal scales. These approaches reveal real-time dynamics of tumor evolution, providing new opportunities for therapeutic intervention. This review synthesizes key advances in understanding tumor heterogeneity: from its cellular origins and molecular mechanisms to its multidimensional manifestation in the tumor microenvironment and from metastatic heterogeneity to the fundamental causes of treatment resistance. We critically examine how these insights are informing novel therapeutic paradigms-including targeting clonal cooperative networks, modulating epigenetic plasticity and reprogramming metabolic adaptations. Finally, we outline future pathways toward precision medicine through the integration of multi-omics data and dynamic monitoring technologies. Ultimately, overcoming tumor heterogeneity necessitates reconceptualizing cancer not as a static collection of cells but as a dynamically evolving ecosystem.
SN  - 2059-3635
SN  - 2095-9907
ER  -