What if a tiny population of cells inside a tumour could survive treatments and reinitiate cancer?
Humans naturally tend to feel relieved when any disease is cured, thanks to advances in biomedical research. Cancer, however, is different. Many cancer survivors, even after completing all the necessary treatments, always have the fear that the cancer will relapse. If chemotherapy or any other treatments can destroy cancer cells, what makes a tumor grow back? Scientists now believe that the answer lies in understanding cancer stem cells, a small but very powerful population of cells (1).
What are Cancer Stem Cells (CSCs)?
Cancer stem cells look surprisingly similar to normal stem cells (NSCs). By definition, both can self-renew, meaning they can produce more copies of themselves. The difference is that the self-renewal in CSCs becomes uncontrolled. This allows CSCs to continuously generate new cancer cells, leading to continued tumor growth. Even though they constitute a relatively small population within a tumor, CSCs can reinitiate cancer after treatment and contribute to the diversity seen among tumor cells.
Origins of CSCs
The origin of CSCs remains a complex and debated topic, highlighting the evolving nature of tumor biology. Although early research suggested that CSCs originate from NSCs with cancer mutations, growing evidence shows that fully differentiated cancer cells can regain stem-like traits. This indicates that CSCs may develop through various pathways influenced by both-
Internal factors, like changes in the DNA sequence itself or changes in how genes are turned on or off.
External factors, including signals from the tumor microenvironment, which is the surrounding environment that can help or hinder the tumor's growth.
Why is it important to study CSCs?
Understanding CSCs is very important as they play a key role in improving cancer treatments by focusing on challenges such as cancer recurrence, therapeutic resistance (2), and metastasis (1). Researchers are working to develop therapies that consider the tumor's structure and resistance mechanisms by learning how these cells survive and adapt.
How can we identify CSCs?
One of the biggest challenges in CSC research is identifying these cells within a tumor. To do this, scientists rely on biomarkers, which are measurable biological indicators that help distinguish CSCs from other cancer cells. These markers help us know better about CSC biology and their unique role in therapeutic resistance and metastasis. The different CSC biomarkers are as follows-
Membrane biomarkers- These are expressed on the cell surface.
Intracellular biomarkers- These markers are found inside cancer stem cells.
How can CSCs resist cancer treatment and the immune response?
One of the most interesting characteristics about CSCs is that they can hide from the treatments by remaining inactive until conditions become favorable again. They can also alter how they utilize energy and activate DNA repair processes to evade the effects of chemotherapy. CSCs that trigger strong immune responses are gradually destroyed by the immune system. This allows CSCs that are less visible to the immune system or those that are inactive to survive into the next phase. Over time, these surviving CSCs grow uncontrollably due to immunosuppressive effectors that suppress the immune response, making it difficult for the immune system to control them.
Can CSCs predict response and survival after chemotherapy?
In a study involving 47 patient with esophageal squamous cell cancer, those who had high levels of a biomarker called CD133 before starting chemotherapy had shorter lifespans after treatment. In contrast, patients with low CD133 levels lived longer. In patients with rectal cancer, those with high levels of CSC markers are more likely to experience distant recurrence than those with lower levels of certain genes.
Can we target Cancer Stem Cells?
Since CSCs contribute to treatment resistance (2) and tumor recurrence, scientists are developing therapies that specifically target these cells. The image below illustrates how CSC-targeted therapies can help reduce tumor progression.
CAR-T-cell therapy: engineered immunotherapy for CSCs
CAR-T cells are T cells that scientists modify in the laboratory to find and destroy tumor cells by targeting specific markers on cell surfaces. With respect to CSCs, some of these overexpressed markers are considered targets for CAR-T-cell therapy.
Cancer vaccines: inducing an anti-CSC immune response
Cancer vaccines help the immune system recognize and eliminate CSCs. Cancer vaccines train the immune system to recognize specific markers on CSCs, creating a long-lasting immune response.
Pathway inhibitors: targeting CSC-specific signaling pathways
CSCs depend on different signaling pathways to maintain their ability to grow, survive, and develop into different cell types (4). These pathways are usually active during embryonic development and help keep tissues healthy. However, when they take a wrong turn in CSCs, it leads to tumor growth. Scientists have developed small-molecule inhibitors to target these pathways.
What are the challenges?
There are several challenges arising from CSC heterogeneity and plasticity. It’s difficult to find reliable biomarkers, which are needed to identify and target these cells. To tackle these issues, a detailed approach is needed that accurately identifies different CSC groups and finds specific markers to enhance treatment effectiveness.
Conclusion
When we start to find answers for why cancer returns even after treatment, we expect it to be because of mutations or drug resistance alone. However, learning about the cancer stem cells makes us realize how this tiny population of cells can be so detrimental. Even though many questions about cancer stem cells remain unanswered, having a thorough understanding of CSCs is necessary to develop more precise therapies that could transform how we approach cancer treatments.
References
1. Lee H, Kim B, Park J, et al. Cancer stem cells: landscape, challenges and emerging therapeutic innovations. Signal Transduct Target Ther. 2025;10:248. doi:10.1038/s41392-025-02360-2
2. Chu X, Tian W, Ning J, et al. Cancer stem cell: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther. 2024;9:170. doi:10.1038/s41392-024-01851-y
3. Harvard Stem Cell Institute. Stem cells and cancer. Accessed October 18, 2026. https://www.hsci.harvard.edu/stem-cells-and-cancer
4. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14(3):275-291. doi:10.1016/j.stem.2014.02.006
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