CANCER STEM CELLS AND THERAPEUTIC RESISTANCE: BIOLOGICAL MECHANISMS AND EMERGING TREATMENT STRATEGIES
Keywords:
Cancer stem cells, Therapeutic resistance, Tumour microenvironment, ignalling pathways, Targeted therapy
Abstract
Cancer stem cells (CSCs) are a unique subpopulation of tumour cells that possess self-renewal, differentiation, tumour initiating and adaptive properties that play a major role in the progression, therapeutic resistance and disease relapse. They survive to anticancer treatment due to various biological mechanisms, such as increased drug efflux, highly efficient DNA repair, resistance to apoptosis, cellular quiescence, metabolic reprogramming, epigenetic control, and adaptation to oxidative stress. In addition, major signalling pathways including Wnt/beta-catenin, Notch, Hedgehog, PI3K/AKT/mTOR, JAK/STAT and NF-kB play a role in regulating CSC behaviour. Moreover, the tumour microenvironment supplies protection signals via hypoxia, stromal cells, immune cells, extracellular matrix, epithelial–mesenchymal transition and the exchange of extracellular vesicles. These mechanisms enable CSCs to be involved in resistance to chemotherapy, radiotherapy, targeted therapy, immunotherapy, and endocrine therapy. New therapeutic strategies thus focus on the eradication of CSCs through targeting of cell surface markers, the disruption of signalling pathways involved in stemness, modification of cellular metabolism, induction of differentiation, immune-mediated elimination, and application of drug delivery strategies using nanotechnology and combination therapies. Yet these successes have been complicated by CSC heterogeneity, phenotypic plasticity, and the variability and similarities of markers with normal stem cells. A better understanding of CSC biology and resistance mechanisms is crucial to designing more accurate and persistent therapeutic options to further lower recurrence and enhance long-term cancer control.
Downloads
Download data is not yet available.
References
1.Alizadeh, H., Akbarabadi, P., Dadfar, A., Tareh, M. R., & Soltani, B. (2025). A comprehensive overview of ovarian cancer stem cells: correlation with high recurrence rate, underlying mechanisms, and therapeutic opportunities. Molecular Cancer, 24(1), 135.
2.Alves, A. L. V., Gomes, I. N., Carloni, A. C., Rosa, M. N., Da Silva, L. S., Evangelista, A. F., ... & Silva, V. A. O. (2021). Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. Stem cell research & therapy, 12(1), 206.
3.Aramini, B., Masciale, V., Grisendi, G., Bertolini, F., Maur, M., Guaitoli, G., ... & Haider, K. H. (2022). Dissecting tumor growth: the role of cancer stem cells in drug resistance and recurrence. Cancers, 14(4), 976.
4.Atashzar, M. R., Baharlou, R., Karami, J., Abdollahi, H., Rezaei, R., Pourramezan, F., & Zoljalali Moghaddam, S. H. (2020). Cancer stem cells: A review from origin to therapeutic implications. Journal of cellular physiology, 235(2), 790-803.
5.Chu, D. T., Nguyen, T. T., Tien, N. L. B., Tran, D. K., Jeong, J. H., Anh, P. G., ... & Dinh, T. C. (2020). Recent progress of stem cell therapy in cancer treatment: molecular mechanisms and potential applications. Cells, 9(3), 563.
6.Das, P. K., Islam, F., & Lam, A. K. (2020). The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells, 9(6), 1392.
7.Ferrari, P., Scatena, C., Ghilli, M., Bargagna, I., Lorenzini, G., & Nicolini, A. (2022). Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC. International journal of molecular sciences, 23(3), 1665.
8.Francescangeli, F., De Angelis, M. L., Rossi, R., Cuccu, A., Giuliani, A., De Maria, R., & Zeuner, A. (2023). Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution. Cancer and Metastasis Reviews, 42(1), 197-215.
9.Gao, Q., Zhan, Y., Sun, L., & Zhu, W. (2023). Cancer stem cells and the tumor microenvironment in tumor drug resistance. Stem Cell Reviews and Reports, 19(7), 2141-2154.
10.Garg, P., Malhotra, J., Kulkarni, P., Horne, D., Salgia, R., & Singhal, S. S. (2024). Emerging therapeutic strategies to overcome drug resistance in cancer cells. Cancers, 16(13), 2478.
11.Gooding, A. J., & Schiemann, W. P. (2020). Epithelial–mesenchymal transition programs and cancer stem cell phenotypes: mediators of breast cancer therapy resistance. Molecular Cancer Research, 18(9), 1257-1270.
12.Gu, Y., Yang, R., Zhang, Y., Guo, M., Takehiro, K., Zhan, M., ... & Wang, H. (2025). Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer. Molecular Biomedicine, 6(1), 2.
13.Haddadin, L., & Sun, X. (2025). Stem cells in cancer: from mechanisms to therapeutic strategies. Cells, 14(7), 538.
14.Huang, T., Song, X., Xu, D., Tiek, D., Goenka, A., Wu, B., ... & Cheng, S. Y. (2020). Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics, 10(19), 8721.
15.Jin, M. L., & Jeong, K. W. (2023). Histone modifications in drug-resistant cancers: From a cancer stem cell and immune evasion perspective. Experimental & Molecular Medicine, 55(7), 1333-1347.
16.Kaur, R., Bhardwaj, A., & Gupta, S. (2023). Cancer treatment therapies: traditional to modern approaches to combat cancers. Molecular biology reports, 50(11), 9663-9676.
17.Keyvani-Ghamsari, S., Khorsandi, K., Rasul, A., & Zaman, M. K. (2021). Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clinical Epigenetics, 13(1), 120.
18.Kilmister, E. J., Koh, S. P., Weth, F. R., Gray, C., & Tan, S. T. (2022). Cancer metastasis and treatment resistance: mechanistic insights and therapeutic targeting of cancer stem cells and the tumor microenvironment. Biomedicines, 10(11), 2988.
19.Lee, H., Kim, B., Park, J., Park, S., Yoo, G., Yum, S., ... & Youn, B. (2025). Cancer stem cells: landscape, challenges and emerging therapeutic innovations. Signal transduction and targeted therapy, 10(1), 248.
20.Li, Y. R., Fang, Y., Lyu, Z., Zhu, Y., & Yang, L. (2023). Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies. Journal of translational medicine, 21(1), 686.
21.Li, Y., Wang, Z., Ajani, J. A., & Song, S. (2021). Drug resistance and Cancer stem cells. Cell Communication and Signaling, 19(1), 19.
22.Lin, Z., Wu, Y., Xu, Y., Li, G., Li, Z., & Liu, T. (2022). Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Molecular cancer, 21(1), 179.
23.Mai, Y., Su, J., Yang, C., Xia, C., & Fu, L. (2023). The strategies to cure cancer patients by eradicating cancer stem-like cells. Molecular cancer, 22(1), 171.
24.Manni, W., & Min, W. (2022). Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm, 3(4), e176.
25.Marine, J. C., Dawson, S. J., & Dawson, M. A. (2020). Non-genetic mechanisms of therapeutic resistance in cancer. Nature Reviews Cancer, 20(12), 743-756.
26.Pan, Y., Yuan, C., Zeng, C., Sun, C., Xia, L., Wang, G., ... & Ding, Z. Y. (2025). Cancer stem cells and niches: challenges in immunotherapy resistance. Molecular cancer, 24(1), 52.
27.Saha, T., & Lukong, K. E. (2022). Breast cancer stem-like cells in drug resistance: a review of mechanisms and novel therapeutic strategies to overcome drug resistance. Frontiers in oncology, 12, 856974.
28.Saw, P. E., Liu, Q., Wong, P. P., & Song, E. (2024). Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell, 31(8), 1101-1112.
29.Shan, C., Liang, Y., Wang, K., & Li, P. (2024). Mesenchymal stem cell-derived extracellular vesicles in cancer therapy resistance: from biology to clinical opportunity. International Journal of Biological Sciences, 20(1), 347.
30.Shi, Z. D., Pang, K., Wu, Z. X., Dong, Y., Hao, L., Qin, J. X., ... & Han, C. H. (2023). Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduction and Targeted Therapy, 8(1), 113.
31.Song, J., Yang, P., Chen, C., Ding, W., Tillement, O., Bai, H., & Zhang, S. (2025). Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance. Signal transduction and targeted therapy, 10(1), 219.
32.Soragni, A., Knudsen, E. S., O’Connor, T. N., Tognon, C. E., Tyner, J. W., Gini, B., ... & National Cancer Institute (NCI) Acquired Resistance to Therapy Network (ARTNet). (2025). Acquired resistance in cancer: towards targeted therapeutic strategies. Nature Reviews Cancer, 25(8), 613-633.
33.Stelmach, P., & Trumpp, A. (2023). Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica, 108(2), 353.
34.Tan, Y., Qin, S., Zhang, Z., Liu, Y., Zhou, L., Li, B., ... & Jing, J. (2025). Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies. MedComm–Oncology, 4(1), e70009.
35.Terraneo, N., Jacob, F., Dubrovska, A., & Grünberg, J. (2020). Novel therapeutic strategies for ovarian cancer stem cells. Frontiers in oncology, 10, 501598.
36.Yang, L., Shi, P., Zhao, G., Xu, J., Peng, W., Zhang, J., ... & Cui, H. (2020). Targeting cancer stem cell pathways for cancer therapy. Signal transduction and targeted therapy, 5(1), 8.
37.Yang, Q., Xu, J., Gu, J., Shi, H., Zhang, J., Zhang, J., ... & Zhang, X. (2022). Extracellular vesicles in cancer drug resistance: roles, mechanisms, and implications. Advanced Science, 9(34), 2201609.
38.Zhang, S., Yang, R., Ouyang, Y., Shen, Y., Hu, L., & Xu, C. (2023). Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer biology & medicine, 20(12), 985-1020.
39.Zheng, Y., Wang, L., Yin, L., Yao, Z., Tong, R., Xue, J., & Lu, Y. (2022). Lung cancer stem cell markers as therapeutic targets: an update on signaling pathways and therapies. Frontiers in oncology, 12, 873994.
40.Zhou, H. M., Zhang, J. G., Zhang, X., & Li, Q. (2021). Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal transduction and targeted therapy, 6(1), 62.
2.Alves, A. L. V., Gomes, I. N., Carloni, A. C., Rosa, M. N., Da Silva, L. S., Evangelista, A. F., ... & Silva, V. A. O. (2021). Role of glioblastoma stem cells in cancer therapeutic resistance: a perspective on antineoplastic agents from natural sources and chemical derivatives. Stem cell research & therapy, 12(1), 206.
3.Aramini, B., Masciale, V., Grisendi, G., Bertolini, F., Maur, M., Guaitoli, G., ... & Haider, K. H. (2022). Dissecting tumor growth: the role of cancer stem cells in drug resistance and recurrence. Cancers, 14(4), 976.
4.Atashzar, M. R., Baharlou, R., Karami, J., Abdollahi, H., Rezaei, R., Pourramezan, F., & Zoljalali Moghaddam, S. H. (2020). Cancer stem cells: A review from origin to therapeutic implications. Journal of cellular physiology, 235(2), 790-803.
5.Chu, D. T., Nguyen, T. T., Tien, N. L. B., Tran, D. K., Jeong, J. H., Anh, P. G., ... & Dinh, T. C. (2020). Recent progress of stem cell therapy in cancer treatment: molecular mechanisms and potential applications. Cells, 9(3), 563.
6.Das, P. K., Islam, F., & Lam, A. K. (2020). The roles of cancer stem cells and therapy resistance in colorectal carcinoma. Cells, 9(6), 1392.
7.Ferrari, P., Scatena, C., Ghilli, M., Bargagna, I., Lorenzini, G., & Nicolini, A. (2022). Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC. International journal of molecular sciences, 23(3), 1665.
8.Francescangeli, F., De Angelis, M. L., Rossi, R., Cuccu, A., Giuliani, A., De Maria, R., & Zeuner, A. (2023). Dormancy, stemness, and therapy resistance: interconnected players in cancer evolution. Cancer and Metastasis Reviews, 42(1), 197-215.
9.Gao, Q., Zhan, Y., Sun, L., & Zhu, W. (2023). Cancer stem cells and the tumor microenvironment in tumor drug resistance. Stem Cell Reviews and Reports, 19(7), 2141-2154.
10.Garg, P., Malhotra, J., Kulkarni, P., Horne, D., Salgia, R., & Singhal, S. S. (2024). Emerging therapeutic strategies to overcome drug resistance in cancer cells. Cancers, 16(13), 2478.
11.Gooding, A. J., & Schiemann, W. P. (2020). Epithelial–mesenchymal transition programs and cancer stem cell phenotypes: mediators of breast cancer therapy resistance. Molecular Cancer Research, 18(9), 1257-1270.
12.Gu, Y., Yang, R., Zhang, Y., Guo, M., Takehiro, K., Zhan, M., ... & Wang, H. (2025). Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer. Molecular Biomedicine, 6(1), 2.
13.Haddadin, L., & Sun, X. (2025). Stem cells in cancer: from mechanisms to therapeutic strategies. Cells, 14(7), 538.
14.Huang, T., Song, X., Xu, D., Tiek, D., Goenka, A., Wu, B., ... & Cheng, S. Y. (2020). Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics, 10(19), 8721.
15.Jin, M. L., & Jeong, K. W. (2023). Histone modifications in drug-resistant cancers: From a cancer stem cell and immune evasion perspective. Experimental & Molecular Medicine, 55(7), 1333-1347.
16.Kaur, R., Bhardwaj, A., & Gupta, S. (2023). Cancer treatment therapies: traditional to modern approaches to combat cancers. Molecular biology reports, 50(11), 9663-9676.
17.Keyvani-Ghamsari, S., Khorsandi, K., Rasul, A., & Zaman, M. K. (2021). Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cells resistance. Clinical Epigenetics, 13(1), 120.
18.Kilmister, E. J., Koh, S. P., Weth, F. R., Gray, C., & Tan, S. T. (2022). Cancer metastasis and treatment resistance: mechanistic insights and therapeutic targeting of cancer stem cells and the tumor microenvironment. Biomedicines, 10(11), 2988.
19.Lee, H., Kim, B., Park, J., Park, S., Yoo, G., Yum, S., ... & Youn, B. (2025). Cancer stem cells: landscape, challenges and emerging therapeutic innovations. Signal transduction and targeted therapy, 10(1), 248.
20.Li, Y. R., Fang, Y., Lyu, Z., Zhu, Y., & Yang, L. (2023). Exploring the dynamic interplay between cancer stem cells and the tumor microenvironment: implications for novel therapeutic strategies. Journal of translational medicine, 21(1), 686.
21.Li, Y., Wang, Z., Ajani, J. A., & Song, S. (2021). Drug resistance and Cancer stem cells. Cell Communication and Signaling, 19(1), 19.
22.Lin, Z., Wu, Y., Xu, Y., Li, G., Li, Z., & Liu, T. (2022). Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Molecular cancer, 21(1), 179.
23.Mai, Y., Su, J., Yang, C., Xia, C., & Fu, L. (2023). The strategies to cure cancer patients by eradicating cancer stem-like cells. Molecular cancer, 22(1), 171.
24.Manni, W., & Min, W. (2022). Signaling pathways in the regulation of cancer stem cells and associated targeted therapy. MedComm, 3(4), e176.
25.Marine, J. C., Dawson, S. J., & Dawson, M. A. (2020). Non-genetic mechanisms of therapeutic resistance in cancer. Nature Reviews Cancer, 20(12), 743-756.
26.Pan, Y., Yuan, C., Zeng, C., Sun, C., Xia, L., Wang, G., ... & Ding, Z. Y. (2025). Cancer stem cells and niches: challenges in immunotherapy resistance. Molecular cancer, 24(1), 52.
27.Saha, T., & Lukong, K. E. (2022). Breast cancer stem-like cells in drug resistance: a review of mechanisms and novel therapeutic strategies to overcome drug resistance. Frontiers in oncology, 12, 856974.
28.Saw, P. E., Liu, Q., Wong, P. P., & Song, E. (2024). Cancer stem cell mimicry for immune evasion and therapeutic resistance. Cell Stem Cell, 31(8), 1101-1112.
29.Shan, C., Liang, Y., Wang, K., & Li, P. (2024). Mesenchymal stem cell-derived extracellular vesicles in cancer therapy resistance: from biology to clinical opportunity. International Journal of Biological Sciences, 20(1), 347.
30.Shi, Z. D., Pang, K., Wu, Z. X., Dong, Y., Hao, L., Qin, J. X., ... & Han, C. H. (2023). Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies. Signal Transduction and Targeted Therapy, 8(1), 113.
31.Song, J., Yang, P., Chen, C., Ding, W., Tillement, O., Bai, H., & Zhang, S. (2025). Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance. Signal transduction and targeted therapy, 10(1), 219.
32.Soragni, A., Knudsen, E. S., O’Connor, T. N., Tognon, C. E., Tyner, J. W., Gini, B., ... & National Cancer Institute (NCI) Acquired Resistance to Therapy Network (ARTNet). (2025). Acquired resistance in cancer: towards targeted therapeutic strategies. Nature Reviews Cancer, 25(8), 613-633.
33.Stelmach, P., & Trumpp, A. (2023). Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica, 108(2), 353.
34.Tan, Y., Qin, S., Zhang, Z., Liu, Y., Zhou, L., Li, B., ... & Jing, J. (2025). Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies. MedComm–Oncology, 4(1), e70009.
35.Terraneo, N., Jacob, F., Dubrovska, A., & Grünberg, J. (2020). Novel therapeutic strategies for ovarian cancer stem cells. Frontiers in oncology, 10, 501598.
36.Yang, L., Shi, P., Zhao, G., Xu, J., Peng, W., Zhang, J., ... & Cui, H. (2020). Targeting cancer stem cell pathways for cancer therapy. Signal transduction and targeted therapy, 5(1), 8.
37.Yang, Q., Xu, J., Gu, J., Shi, H., Zhang, J., Zhang, J., ... & Zhang, X. (2022). Extracellular vesicles in cancer drug resistance: roles, mechanisms, and implications. Advanced Science, 9(34), 2201609.
38.Zhang, S., Yang, R., Ouyang, Y., Shen, Y., Hu, L., & Xu, C. (2023). Cancer stem cells: a target for overcoming therapeutic resistance and relapse. Cancer biology & medicine, 20(12), 985-1020.
39.Zheng, Y., Wang, L., Yin, L., Yao, Z., Tong, R., Xue, J., & Lu, Y. (2022). Lung cancer stem cell markers as therapeutic targets: an update on signaling pathways and therapies. Frontiers in oncology, 12, 873994.
40.Zhou, H. M., Zhang, J. G., Zhang, X., & Li, Q. (2021). Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal transduction and targeted therapy, 6(1), 62.
Published
2026-08-25
How to Cite
Arjun R. Patel, & William C. Zhang. (2026). CANCER STEM CELLS AND THERAPEUTIC RESISTANCE: BIOLOGICAL MECHANISMS AND EMERGING TREATMENT STRATEGIES. IJRDO - JOURNAL OF BIOLOGICAL SCIENCE, 12(3), 1-20. https://doi.org/10.69980/bs.v12i3.6810
Section
Articles
Copyright (c) 2026 IJRDO - JOURNAL OF BIOLOGICAL SCIENCE
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
.png)
