Epithelial-mesenchymal transition in cancer metastasis: Molecular mechanisms, microenvironmental regulation, and therapeutic targeting

Abstract

Epithelial-mesenchymal transition is a crucial driver of cancer metastasis, enabling cancer cells to acquire invasive and migratory characteristics. This review synthesizes the molecular mechanisms underlying EMT, focusing on the transcription factors Snail, ZEB, and Twist, as well as the signaling pathways TGF-β/Smad and PI3K/Akt that regulate phenotypic plasticity. Components of the tumor microenvironment, including cytokines, hypoxia, and cancer-associated fibroblasts, synergistically activate EMT through dynamic interactions with oncogenic signaling pathways. The heterogeneity of EMT across different cancer types, such as hormone-mediated regulation in breast cancer and the involvement of non-coding RNAs in gastric malignancies, highlights its context-dependent role. Emerging therapies targeting EMT include small-molecule inhibitors, natural compounds, and herbal formulations, which aim to reverse EMT markers such as E-cadherin loss and vimentin upregulation, thereby sensitizing cancers to chemotherapy. Combinatorial approaches that integrate EMT suppression with conventional treatments show promise in overcoming drug resistance. However, challenges remain in clinical translation due to the plasticity of EMT and the adaptability of cancers. Future efforts should prioritize biomarker-driven strategies, and multi-omics approaches to refine the therapeutic targeting of EMT in metastatic cancers.

Keywords

Epithelial-Mesenchymal Transition / Cancer Metastasis / Molecular Mechanisms / Tumor Microenvironment / Therapeutic Target

Declarations

Not applicable.

CRediT authorship contribution statement

guo shuai: Writing - review & editing, Writing - original draft, Funding acquisition, Conceptualization. Yinuo Liu: Writing - review & editing, Writing - original draft, Software, Investigation, Data curation, Conceptualization. Zhouye Ma: Investigation. Yue Chen: Investigation. Yuwei Cui: Investigation. Haifu Wan: Investigation. Xuzhao Wang: Writing - review & editing, Conceptualization. Xianjiang Kang: Writing - review & editing, Conceptualization.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the National Key Research and Development Plan of China (Grant No. 2023YFF1205500), Natural Science Foundation of Hebei Province of China (Grant No. C2025201028), Science Research Project of Hebei Education Department (Grant No. BJK2024014), and Natural Science Interdisciplinary Research Program of Hebei University (DXK202202).

Declaration of Competing Interest

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Authors' other information

Not applicable.

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