The Tumour Is an Ecosystem: How the Microenvironment Shapes Resistance
Cancer cells do not survive alone. Explore how blood vessels, immune cells and surrounding tissue can support resistance—and how researchers are finding ways to disrupt that support.
Page 7 of the hub that unpacks the 2026 Cancer Stem Cells and Drug Resistance Review.
A tumour is not simply a lump of cancer cells. It is more like a small, changing neighbourhood: cancer cells live alongside blood vessels, immune cells, fibroblasts, structural fibres, chemical signals and areas with very different supplies of oxygen and nutrients. Together, these surroundings are called the tumour microenvironment, or TME. The key point is that cancer cells can shape this neighbourhood—and the neighbourhood can, in turn, help some cancer cells survive treatment, change state or avoid immune attack.
For someone reading this after progression, this helps make sense of an often-frustrating reality: a treatment can be biologically active against cancer cells, yet still struggle because some parts of the tumour are difficult for drugs or immune cells to reach, or because nearby cells are sending survival signals. This is not a sign that treatment was pointless. It is one reason researchers increasingly study the tumour and its local environment together, rather than treating the cancer cell as though it exists in isolation.
A useful image: Cancer cells are not living alone in an empty field. They are more like a group of people inside a fortified, constantly changing town. The town has roads and supply lines, protective walls, communication networks, emergency shelters and neighbours who may be persuaded—or pressured—to help the tumour survive. The hopeful part is that this support system is not fixed: researchers are learning how to interrupt its protective signals, improve access for treatments and help immune cells find their way into the tumour.
Low oxygen: the survival zone
Fast-growing tumours can outgrow their blood supply. This produces pockets of low oxygen, called hypoxia. Hypoxia is not simply an uncomfortable condition that cancer cells have to endure. It can change which cells survive and how they behave.
Low-oxygen regions may be harder for some drugs to reach. They can also activate a cellular emergency-response program, driven in part by a protein called HIF-1α. This program can alter metabolism, encourage slower or more treatment-tolerant states, strengthen stress responses, support EMT-related plasticity and influence how cancer cells communicate with nearby immune and stromal cells.
In the "house in a storm" image, hypoxia is like a long power outage in the neighbourhood. Some houses cannot cope. Others switch to backup power, conserve resources, turn on their emergency two-way radio and become better prepared to wait out the crisis. In cancer, this adaptability may allow a small population of cells to persist through a treatment that is highly effective against more exposed, rapidly growing cells.
This is why scientists are investigating ways to improve drug delivery, alter abnormal tumour blood vessels, interfere with hypoxia-response signalling, change cancer-cell metabolism or pair treatment with immunotherapy. These approaches are still highly cancer-specific and mostly investigational; no person should attempt to "treat hypoxia" with an off-label drug, oxygen protocol or supplement based on this biology alone.
Blood vessels: supply lines and shelter
Blood vessels have a complicated role in cancer. They can deliver oxygen and nutrients that allow tumours to grow, but they can also be abnormal, leaky, disorganised or poorly functioning—which can make drug delivery uneven and create hypoxic areas.
The review describes a perivascular niche: an area near blood vessels where some cancer cells may receive signals that support survival, self-renewal, slow cycling and treatment tolerance. In some cancers—particularly in brain-tumour research, but not only there—cancer cells can interact closely with endothelial cells lining blood vessels and with nearby support cells.
There is another important concept called vessel co-option. Instead of forcing the body to grow new vessels, some tumours can attach themselves to and use blood vessels that were already present in the surrounding normal tissue. This matters because anti-angiogenic drugs are designed mainly to disrupt the making of new blood vessels. If a tumour uses existing vessels instead, it may partly bypass that strategy. Vessel co-option has been observed in several tumour types and in metastatic disease, and it is considered one potential contributor to resistance to anti-angiogenic therapy.
What this does not mean: Blood-vessel-targeting drugs are ineffective or inappropriate. They can be valuable treatments in defined cancer settings. It means that tumours can use more than one vascular survival strategy, so response and resistance need to be understood in the context of the individual cancer.
When neighbours are recruited
The tumour microenvironment includes cells that normally have useful roles in healing, tissue maintenance and immune defence. Cancer can sometimes influence those cells so that they provide protection rather than attack.
Immune cells
The immune system is not one thing. Some immune cells can recognise and attack cancer. Others may be recruited or reprogrammed into states that reduce effective anti-tumour immunity.
The review discusses:
Tumour-associated macrophages (TAMs): immune cells that, in some tumour contexts, can release signals supporting tumour growth, blood-vessel changes, tissue remodelling, EMT-like plasticity and immune suppression.
Regulatory T cells (Tregs): immune cells that normally prevent excessive immune reactions, but which can also dampen anti-tumour immune responses when enriched in a tumour.
Myeloid-derived suppressor cells (MDSCs): immature myeloid cells that can restrain T-cell activity and contribute to an immune-suppressive environment.
This is one reason immunotherapy is not simply a matter of "switching on" the immune system. A tumour may have multiple ways to keep T cells out, exhaust them, reduce their activity or change the local conditions so that they cannot work effectively.
Fibroblasts and the structural environment
Fibroblasts normally help maintain and repair tissue. In tumours, some become cancer-associated fibroblasts, or CAFs. These cells can produce a dense meshwork of collagen and other material called the extracellular matrix, or ECM.
Think of the ECM as the neighbourhood's physical scaffolding and roads. In some cancers, it can become unusually dense and stiff. That may:
Create a physical barrier that makes drug penetration more difficult.
Limit the movement of cancer-fighting T cells into parts of the tumour.
Send mechanical and chemical signals that affect cancer-cell behaviour.
Support stem-like states, EMT-related plasticity and resistance in certain tumour contexts.
However, this is not a simple "fibroblasts are bad" story. CAFs are diverse. Some may help restrain tumour growth in particular settings, and attempts to remove whole fibroblast populations have sometimes had unintended consequences in preclinical studies. Researchers are therefore increasingly exploring ways to reprogram, normalise or selectively target harmful stromal signals rather than indiscriminately remove all support tissue.
Why this changes the questions
CSC research is no longer asking only:
"How do we kill the cancer cell that is resistant?"
It is also asking:
How can we interrupt the survival messages a resistant cell receives?
Can we improve drug delivery into protected tumour regions?
Can we change the abnormal blood-vessel, low-oxygen or dense-stroma conditions that support treatment tolerance?
Can we help immune cells enter the tumour and remain active there?
Can we reduce the signals that encourage cancer cells to switch into stem-like, treatment-tolerant states?
Which combinations can do this safely without damaging normal tissue repair, blood vessels or immune function?
That shift—from treating a cancer cell alone to treating a cancer ecosystem—is one of the most active areas of current oncology research. It also explains why combinations are increasingly important: a treatment may need to target actively dividing tumour cells while another component improves immune attack, blocks a survival pathway, disrupts stromal support or addresses a molecular vulnerability.
What this means after progression
A scan showing progression does not tell us exactly which part of the tumour ecosystem is involved. It may be driven by tumour-cell mutations, CSC-like state changes, drug delivery, immune escape, stromal support—or several mechanisms at once. At present, most TME and CSC features are not routine tests that can direct treatment on their own.
Still, the biology supports constructive questions when a treatment stops working:
"Does the pattern of my progression suggest that repeat molecular testing, a biopsy, or a clinical-trial review could be useful?"
"Are there established therapies or trials for my cancer that are relevant to immune response, angiogenesis, stromal biology, hypoxia, resistance mechanisms or tumour-cell plasticity?"
"Could a multidisciplinary review—including pathology, medical oncology, radiation oncology, surgery, genetics and an oncology pharmacist—identify options we have not yet considered?"
The most useful takeaway is not that every tumour microenvironment can already be measured or "fixed." It is that treatment resistance is increasingly understood as a shared problem between cancer cells and their surroundings. That understanding is opening new strategies—but most require careful testing in clinical trials before they can be considered safe or effective for individuals.
Further reading
Key paper: Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets Hamdy H, Li Y, Li C, et al. Molecular Biomedicine. 2026;7:114. https://doi.org/10.1186/s43556-026-00516-2 The anchor review for CSC niches, hypoxia, perivascular support, immune escape, fibroblasts and resistance.
Tumor microenvironment as niche constructed by cancer stem cells: Breaking the ecosystem to combat cancer Journal of Advanced Research. 2025;71:279–296. https://doi.org/10.1016/j.jare.2024.06.014 A useful overview of the two-way relationship between CSCs and the tumour microenvironment, including hypoxia, immune cells, fibroblasts and treatment resistance.
Multi-omics dissection of tumor microenvironment-mediated drug resistance: mechanisms and therapeutic reprogramming Frontiers in Pharmacology. 2025;16:1634413. https://doi.org/10.3389/fphar.2025.1634413 Covers hypoxia, abnormal tumour blood vessels, metabolic stress, immune suppression and CSC-protective niches, as well as emerging multi-omics approaches to studying them.
Vessel co-option in cancer Kuczynski EA, Vermeulen PB, Pezzella F, et al. Nature Reviews Clinical Oncology. 2019;16:469–493. https://doi.org/10.1038/s41571-019-0181-9 The key review for understanding how some tumours use existing blood vessels rather than making new ones, and why this can contribute to resistance to anti-angiogenic therapy.
Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases Frentzas S, Simoneau E, Bridgeman VL, et al. Nature Medicine. 2016;22:1294–1302. https://doi.org/10.1038/nm.4197 Important patient-tissue and experimental evidence linking vessel co-option with poorer response to bevacizumab in colorectal-cancer liver metastases.
Cancer-associated fibroblasts in cancer drug resistance and cancer progression: a review Masuda H. Cell Death Discovery. 2025;11:341. https://doi.org/10.1038/s41420-025-02566-x Helpful for explaining how CAFs can build dense extracellular matrix, limit drug and T-cell penetration, support EMT and contribute to immune suppression and treatment resistance.
The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors Drug Resistance Updates. 2025;82:101273. https://doi.org/10.1016/j.drup.2025.101273 Current review of CAF heterogeneity, stromal signalling, immune suppression, cancer stemness, ECM remodelling and emerging clinical approaches to CAF-directed therapy.
Novel anti-tumor strategies: targeting the crosstalk between cancer stem cells and cancer-associated fibroblasts to resist drug resistance Shen Y, Sun Y, Li X, et al. Cancer Drug Resistance. 2026;9:3. https://doi.org/10.20517/cdr.2025.189 A useful newer review focusing specifically on the reciprocal CSC–CAF relationship and why researchers are exploring strategies that target both resistant cancer-cell states and their supporting stromal environment.
This information is for education only. It is not medical advice, diagnosis, or treatment. Please speak with a qualified clinician before making changes to care, medication, or supplement use.