When we think about a cancer diagnosis, it is natural to associate the worst-case scenario with a well-known word: metastasis. This is a process through which some cells manage to leave the primary tumor, travel through the body, and establish themselves in other tissues.
Today, metastasis remains responsible for the majority of cancer-related deaths and represents one of the greatest challenges in modern oncology. Although it may sound contradictory, despite appearing to be common and consequential in most types of cancer, the reality is that, for a tumor cell, achieving metastasis is highly unlikely. It must overcome numerous biological barriers, survive adverse conditions, partially escape the immune system, and ultimately find a suitable environment in which to establish itself.
Escaping the tumor is only the first step
The cells that make up a tumor are normally surrounded by other cells and by a structure that provides them with support. To leave this environment, they need to change part of their behavior. Some tumor cells can activate molecular programs that reduce their adhesion to neighboring cells and increase their ability to move and invade tissues.
One of these programs is known as the epithelial–mesenchymal transition, or EMT, and regulatory proteins such as SNAIL and TWIST can participate in this process.
However, escaping the primary tumor does not guarantee success. The cell must reach a blood or lymphatic vessel, withstand the physical forces of circulation, avoid being destroyed by the immune system along the way, and then exit the vessel again at another location in the body. Many tumor cells fail to complete this journey. Those that do still face perhaps the greatest challenge: surviving in a completely different tissue.
Not all organs are equally favorable
More than a century ago, a metaphor emerged that remains very useful for explaining metastasis: the “seed and soil” hypothesis. The tumor cell represents the seed, while the organ where it attempts to establish itself represents the soil.
A seed can be perfectly viable and still fail to grow if it falls on unfavorable ground. Similarly, a cancer cell can reach different organs, but it will only be able to thrive if it encounters conditions that favor its survival.
This helps explain why some cancers show a preference for certain organs. Specific chemical signals can act as guidance systems. For example, the CXCL12–CXCR4 pathway participates in the migration of some tumor cells toward tissues rich in CXCL12, such as the lungs, liver, and bone marrow. Other mechanisms are specifically involved in the colonization of bone, lymph nodes, or the brain.
Therefore, metastasis depends not only on where a cell manages to arrive, but also on how compatible that new environment is with its needs.
The tumor can prepare the ground before its cells arrive
One of the most interesting discoveries of recent decades is that the primary tumor can influence distant organs before metastatic cells reach them.
Tumors release molecules capable of traveling through the body and modifying cells in other tissues. As a result, changes can occur in blood vessels, fibroblasts, immune cells, and structural components of the organ. This previously modified environment is known as the pre-metastatic niche.
Small vesicles released by cells can transport different molecules and act as messengers between tissues, modifying the behavior of fibroblasts, blood vessel cells, and certain immune cells in distant organs. In doing so, they can help create conditions that are more favorable for future colonization.
The tumor does not necessarily wait passively for a cell to successfully establish itself in another organ; it may also contribute beforehand to modifying that “soil.”
The microenvironment is also part of cancer
A tumor is not made up exclusively of cancer cells. As mentioned in previous blogs, an entire ecosystem exists around it, composed of immune cells, fibroblasts, blood vessels, signaling molecules, and a structure known as the extracellular matrix.
This matrix acts as a kind of scaffold that keeps tissues organized. Tumor cells and the cells surrounding them can modify it using different enzymes. Some, such as matrix metalloproteinases, break down structural components and can facilitate cell movement. Others alter tissue stiffness and contribute to the release of signals stored within the matrix.
For this reason, metastasis is currently considered to arise from a continuous interaction between the tumor cell, the microenvironment, and the body. Processes such as tissue remodeling, the formation of new blood vessels, metabolic adaptation, and immune regulation combine to determine whether a cell is able to survive and expand.
The immune system also tries to stop them
As a tumor cell attempts to travel and establish itself, the immune system represents another important barrier. T cells and NK cells, among other components, can recognize and destroy abnormal cells.
Tumor cells, however, can develop mechanisms that make this response more difficult. Some immune cell populations within the microenvironment can even acquire immunosuppressive functions. Immune “brake” signals may also become activated, reducing the ability of T cells to attack the tumor.
Platelets can also participate. During circulation, they can partially surround some tumor cells and help protect them from physical stress and immune surveillance. At the same time, a particularly dense extracellular matrix can act as a barrier that makes it more difficult for immune cells to reach the inside of the tumor.
But the immune system does not always completely eliminate the disease, nor does it necessarily allow it to progress. Sometimes, a kind of balance can develop.
Figure 1.The metastatic cascade is a multistep process in which tumor cells leave the primary tumor, enter and survive in circulation, evade immune surveillance, extravasate, and adapt to a distant microenvironment to establish metastasis.
When cancer becomes “dormant”
One of the most fascinating aspects of metastasis is what is known as tumor dormancy.
Some cancer cells can reach a distant organ and remain there for long periods without forming a clinically detectable metastasis. These cells remain alive, but their growth is stopped or severely limited. Under certain circumstances, this state can persist for years.
There are three main forms of dormancy.
Cellular dormancy: An individual cell temporarily enters a resting state and stops dividing.
Angiogenic dormancy: A small population of tumor cells is present, but its growth is limited because it cannot form enough blood vessels.
Immune-mediated dormancy: The cells may continue attempting to proliferate, but immune surveillance keeps their numbers under control.
These situations are not necessarily independent. The same tumor cell population may transition from one form of dormancy to another depending on the conditions present in the body.
What can wake up a dormant tumor cell?
The fact that a cell is dormant does not mean that it has permanently lost its ability to grow. This state is potentially reversible.
Changes in the surrounding tissue, modifications in growth signals, metabolic alterations, the availability of new blood vessels, or a reduction in the pressure exerted by the immune system could allow some cells to begin proliferating again.
In immune-mediated dormancy, for example, T cells can play an important role in keeping tumor cells under control. However, if these lymphocytes lose functionality or become exhausted, some tumor cells may escape that control and resume their growth.
This phenomenon is one possible biological explanation for why certain cancers can reappear after long periods without clinical evidence of disease.
However, this does not mean that every patient treated for cancer has dormant tumor cells or that recurrence is inevitable. Dormancy depends on the type of tumor, its biological characteristics, the microenvironment, and multiple individual factors.
But is there any way to know?
Finding a disease we still cannot see
One of the major clinical challenges is that these cell populations may be too small to be detected using conventional imaging techniques.
For this reason, there is growing interest in identifying what is known as minimal residual disease. Tools such as liquid biopsy aim to detect tumor-derived signals in blood samples, including circulating tumor DNA or circulating tumor cells.
The challenge is that a dormant population may release extremely small amounts of DNA. Researchers are therefore developing methods capable of detecting more subtle signals, including methylation patterns or characteristics related to the fragmentation of circulating DNA. These technologies are promising, but they still require clinical validation and standardization before they can be widely used to detect metastatic dormancy.
Treating both the seed and the soil
Understanding metastasis as an interaction between tumor cells and their environment is also changing the way scientists think about treatment.
The goal is not only to destroy the cancer cell. It may also be useful to modify the environment that allows that cell to survive.
For this reason, researchers are investigating strategies targeting the immune system, the extracellular matrix, the chemical signals tumor cells use to travel toward specific organs, and the mechanisms that allow cells to enter or exit dormancy. New tools are also being studied to detect residual disease before a visible metastasis develops.
Some of these strategies are still under investigation and do not represent established treatments for all patients. Nevertheless, they reflect an important shift: metastasis is increasingly being viewed as a process that could potentially be targeted at different stages, rather than only after a new tumor has already formed.
Figure 2. The tumor dormancy process can occur through different mechanisms, including cellular, angiogenic, and immune-mediated dormancy, which can limit tumor cell proliferation and metastatic growth for prolonged periods.
Understanding the journey could change how we approach metastasis
Metastasis is not a single event. It is a chain of events in which a cell must escape, travel, survive, adapt, and find suitable conditions.
Many cells will fail to complete this journey. Others may remain dormant for years. Some will be kept under control by the immune system. And only a fraction will eventually form a detectable metastatic lesion.
That is why one of the major questions in current research is no longer simply how to eliminate a metastasis, but how to detect and stop the process before it reaches that point.
Can we identify dormant cells? Can we prevent them from waking up? Is it possible to modify the microenvironment so that an organ becomes unfavorable for tumor colonization? Could we detect microscopic disease years before it becomes visible on an imaging test?
Answering these questions could bring us closer to a form of oncology in which controlling the primary tumor is only one part of treatment, and in which we can also anticipate the mechanisms that allow cancer to survive, hide, and grow again.
Main reference:
Kim D. J. (2026). Molecular and Immune Mechanisms Governing Cancer Metastasis, Including Dormancy, Microenvironmental Niches, and Tumor-Specific Programs. International journal of molecular sciences, 27(2), 875. https://doi.org/10.3390/ijms27020875
Other references:
Wang, X., Luo, X., Xiao, R., Liu, X., Zhou, F., Jiang, D., Bai, J., Cui, M., You, L., & Zhao, Y. (2026). Targeting metabolic-epigenetic-immune axis in cancer: molecular mechanisms and therapeutic implications. Signal transduction and targeted therapy, 11(1), 28. https://doi.org/10.1038/s41392-025-02334-4
Tiwary, K., & Bravo-Cordero, J. J. (2026). Metastasis on pause: How dormant tumor cells stay hidden within the tumor microenvironment and evade immune surveillance. Molecular oncology, 10.1002/1878-0261.70259. Advance online publication. https://doi.org/10.1002/1878-0261.70259
Bakir, M., Dabaliz, A., Dawalibi, A., & Mohammad, K. S. (2025). Microenvironmental and Molecular Pathways Driving Dormancy Escape in Bone Metastases. International journal of molecular sciences, 26(24), 11893. https://doi.org/10.3390/ijms262411893
