Cancer cells can change state: the shift in stem cell research

Cancer stem cells are not simply a fixed group of “hidden cells.” Explore how cancer cells can change state, adapt under treatment pressure—and reveal new vulnerabilities.

Page 6 of the hub that unpacks the 2026 Cancer Stem Cells and Drug Resistance Review.

The most important update in the 2026 review is that researchers are moving away from a simple “fixed hierarchy” picture of cancer stem cells. In the older model, a small, stable population of CSCs sat at the top of the tumour, continually making both more CSCs and the less stem-like cells that form most of the tumour mass. That model still helps explain some cancers—especially particular blood cancers—but it does not fully capture what many solid tumours appear to do under the changing conditions of a living body and during treatment.

The newer model sees stemness as a changeable cell state, not always a permanent identity. A cancer cell that is not currently behaving like a CSC may, under pressure, switch into a more stem-like, slow-growing and treatment-tolerant state. A cell already in a stem-like state may also become more differentiated again. Researchers call this capacity to change behaviour cellular plasticity.

This matters because treatment itself is one of the pressures that can shape a tumour. Other pressures include low oxygen, inflammation, immune attack, poor nutrient supply, altered tissue stiffness and signals from nearby blood vessels, immune cells and fibroblasts. Some cells may already be resistant and survive treatment; others may adapt after treatment begins. Scientists are still working out how much of this reflects true reversible reprogramming versus selection and expansion of pre-existing resistant cell populations. In reality, both processes may occur, and their relative importance differs by cancer type and person.

What this means for patients: A progressing tumour is not necessarily made up of one fixed “bad cell” that was missed. It may be a changing ecosystem of cancer cells using different survival strategies at different times. This is one reason why a treatment that worked initially may later need to be changed, combined with another approach, or reconsidered in light of new molecular testing.

Why a single CSC marker may not be enough

In laboratory studies researchers often use markers such as CD44, CD133, ALDH1 or EpCAM to enrich for cancer cells with stem-like properties. But these markers are not universal CSC labels. They can vary between tumour types, change over time and appear on some normal cells as well as cancer cells.

If cancer cells can change state, removing one marker-positive group may not be sufficient: surviving cells that do not currently carry that marker may sometimes acquire a similar stem-like state later.

The review argues that successful future treatment will probably need to address both the resistant cells themselves and the tumour conditions that help create or protect them.

It is also why a headline claiming that a product “kills cancer stem cells” needs close scrutiny. In a cell dish, researchers can measure a marker or reduce the number of cells able to grow spheres.

In a person, the cancer may have several cell states, different tumour sites, different micro-environments, immune influences, treatment effects and safety limits.

A laboratory result against one CSC marker is not proof that a strategy prevents relapse or improves survival.

EMT: a program of movement and adaptation

One major biological process behind plasticity is epithelial–mesenchymal transition, usually shortened to EMT.

To make the language less intimidating:

Epithelial cells are usually organised, attached to neighbouring cells and structured within a tissue—rather like bricks aligned in a wall.
Mesenchymal-like cells are generally more mobile, flexible and able to move through surrounding tissue.
EMT describes a process in which cancer cells lose some epithelial characteristics and acquire some mesenchymal-like ones.
MET, or mesenchymal–epithelial transition, describes movement back in the other direction.

In cancer, EMT is not usually an on/off switch. Cells often sit somewhere in between: retaining some “attached and organised” features while gaining some “mobile and adaptable” features. These are called hybrid epithelial/mesenchymal, partial EMT, or E/M hybrid states.

Modern single-cell research has helped show why the older either/or picture was too simple: individual tumour cells can display mixed epithelial and mesenchymal gene programs at the same time.

A useful image

Rather than picturing a cancer cell as permanently changing from one thing into another, imagine it as a house changing its settings for a storm.

In its more epithelial state, the cell is like a house firmly connected to a street: anchored to neighbouring cells, structured, specialised and relatively settled in its original tissue. Under pressure—such as low oxygen, inflammation, immune attack or treatment—it may not demolish the house and become something entirely different. It may close its shutters, switch to back-up power, turn on its emergency two-way radio, and become ready to leave if necessary.

In this more mesenchymal-like or hybrid state, the cell may still retain features of its original tissue identity, but it can become less attached, more mobile, better able to tolerate stress and more able to use alternative survival pathways. It may also communicate differently with surrounding immune, blood-vessel and connective-tissue cells.

The important word is plasticity: the cancer cell can adjust its “settings” in response to conditions around it. In some cases, it may later shift back toward a more settled, epithelial-like state—particularly if it reaches a new environment where it can establish growth. This ability to move between states, rather than being permanently one kind of cell, is why researchers think hybrid states may matter in treatment resistance and metastasis.

The 2026 review places particular emphasis on these intermediate states. It describes hybrid E/M cells as potentially highly plastic:

able to respond rapidly to changing conditions,
enter or leave stem-like states and
survive therapies that are effective against less adaptable cancer cells.

Why EMT is being studied so closely

EMT and epithelial–mesenchymal plasticity are linked in research to several features that matter in cancer:

Feature	Why EMT/plasticity may matter
Local invasion	More mobile cells may be better able to move through surrounding tissue
Metastasis	A cell must adapt repeatedly to leave the original tumour, survive travel and establish growth in a different organ
Stem-like behaviour	EMT-associated programs can overlap with self-renewal and treatment-tolerant states
Chemotherapy and targeted-therapy resistance	Plastic cells may grow slowly, avoid apoptosis, activate survival pathways or become less dependent on the original drug target
Radiation resistance	Changes in DNA repair, oxidative-stress handling and cell state may affect survival after radiation
Immunotherapy resistance	EMT-associated states may contribute to immune suppression, reduced immune-cell attack and resistance to checkpoint blockade
Tumour recurrence	A small number of adaptable survivors may repopulate the tumour after initial treatment response

These links are supported by a large body of cell-line and animal research, and by a growing number of associations in patient tumour samples. However, the clinical field is still early: EMT is not yet a routine, stand-alone clinical test that can reliably predict what will happen for an individual person or dictate treatment choice on its own.

A necessary caution about “metastasis genes”

It would be misleading to say that EMT automatically means a cancer will spread, or that every metastatic cancer is permanently mesenchymal. Metastasis is a multistep process.

A cell may need flexibility in both directions: more mesenchymal-like traits to invade and travel, and more epithelial-like traits to settle and grow successfully in a new organ.

This is one reason researchers increasingly use the broader term epithelial–mesenchymal plasticity, or EMP, rather than treating EMT as a one-way journey.

What is changing in the plasticity model research

The plasticity model is changing how scientists think about resistance. Instead of searching only for a new mutation or a single “master CSC marker,” researchers increasingly study:

Treatment-tolerant persister cells: small cell populations that survive initial treatment without necessarily carrying a classic resistance mutation.
Single-cell sequencing: methods that examine gene activity cell by cell rather than averaging signals across a whole tumour.
Spatial biology: methods that show where different cells are located in relation to blood vessels, immune cells, oxygen-poor zones and tumour stroma.
Liquid biopsies and repeated tumour profiling: approaches that may sometimes show how a cancer is evolving during treatment.
Combination strategies: pairing a standard treatment with an approach intended to reduce adaptation, block survival signals, change the microenvironment or improve immune attack.

This does not mean that every person with progression needs repeated biopsies, single-cell sequencing or an “EMT test.” Those tools are still mostly research tools, and the usefulness of repeat testing depends on the cancer type, site of progression, previous testing, likely treatment implications and the safety of obtaining tissue.

But it does support a reasonable and empowering question after progression:

“Could my cancer have changed in a way that makes repeat tissue testing, liquid-biopsy testing, broader genomic profiling, or a clinical-trial review worthwhile now?”

What is being tested

There is no approved, universal “anti-EMT” treatment. Researchers are testing ways to interrupt the signals that encourage plasticity or exploit vulnerabilities of treatment-tolerant cell states.

Research direction	Examples discussed in current literature	Important limitation
Blocking EMT-promoting signals	TGF-β-related approaches, Wnt/β-catenin, Notch and Hedgehog pathway strategies	These pathways also help normal tissues function, so toxicity and compensation by other pathways are major barriers
Targeting the tumour microenvironment	Approaches involving hypoxia, fibroblasts, extracellular matrix, blood vessels and immune-suppressive cells	Most remain experimental; a tumour can use multiple supportive niches
Epigenetic approaches	HDAC, DNMT, EZH2 and other gene-regulation strategies	Some drugs are approved for defined cancers, but using them specifically to reverse CSC plasticity is still being studied
Metabolic approaches	OXPHOS, glycolysis, glutamine, fatty-acid metabolism and redox-balance strategies	Cancer cells may switch fuel sources or use alternative pathways
Immunotherapy combinations	Pairing immune checkpoint inhibitors with treatments intended to alter immune suppression or plasticity	Promising concept, but benefits are highly cancer- and biomarker-specific
Differentiation strategies	Encouraging cells to leave a stem-like state and become more treatment-sensitive	Established in selected blood cancers; far less proven in most solid tumours

The review's key practical point is that one-drug, one-target thinking is unlikely to be enough for a highly adaptable system. Future progress is more likely to come from carefully tested combinations that treat actively growing tumour cells while also limiting resistance, cell-state switching and the protective tumour environment.

What this does—and does not—mean

This section should leave readers better informed, not frightened.

It does mean:

Cancer-cell states can be dynamic, especially under treatment pressure.
Stem-like behaviour and EMT-related plasticity are credible research frameworks for understanding some forms of resistance, recurrence and metastasis.
New technologies are helping researchers observe tumour heterogeneity more closely.
A cancer that progresses may still be worth re-evaluating for biomarkers, molecular changes and relevant clinical trials.

It does not mean:

Standard treatment causes metastasis or is futile because it “only kills the easy cells.”
Every cancer contains a fixed, tiny group of CSCs that can be identified and eliminated by one product.
An “anti-EMT” diet, supplement, detoxification program or fasting regimen has been shown to prevent CSC formation or overcome progression in people.
A laboratory observation about CD44, CD133, ALDH1, EMT or a signalling pathway can be used to select a treatment outside clinical evidence.

The message in the most current research is also the most hopeful one: cancer is adaptable, but that adaptability can reveal vulnerabilities. The job of current oncology research is to identify which vulnerability matters in which cancer, at which time, and how to target it safely enough to improve real patient outcomes.