Immunotherapy can produce long-lasting cancer control for some patients, but it does not work indefinitely for everyone. In some cases, a cancer does not respond from the beginning. In others, the cancer initially shrinks or remains controlled and then starts growing again.
This is known as immunotherapy resistance. Resistance does not necessarily mean that immunotherapy was ineffective or that the treatment was a mistake. Cancer is biologically complex, and tumours can change over time.
If you are learning about cancer immunotherapy, understanding why resistance occurs can help explain why treatment plans sometimes need to change.
*AI-generated image - for illustration only. Clinical accuracy is not guaranteed.
What Does Immunotherapy Resistance Mean?
Immunotherapy resistance means that cancer is not being adequately controlled by an immunotherapy treatment. It can occur in two broad ways.
Primary or Intrinsic Resistance
Some cancers do not respond meaningfully to immunotherapy from the start. This is sometimes called primary resistance or intrinsic resistance.
The immune system may have difficulty recognising the cancer, immune cells may not be able to enter the tumour effectively, or the tumour may have biological features that suppress an immune response. Several different mechanisms can exist within the same tumour, making resistance difficult to predict with a single test.
Acquired Resistance
Other cancers initially respond to immunotherapy but later begin growing again. This is known as acquired resistance. During treatment, cancer cells and the surrounding tumour environment can change.
A small population of cancer cells that was less sensitive to treatment may survive and eventually become dominant. Genetic and other biological changes can also allow the tumour to escape immune attack.
*AI-generated image - for illustration only. Clinical accuracy is not guaranteed.
Why Can Cancer Become Resistant to Immunotherapy?
There is no single explanation. Immunotherapy resistance can result from changes in the cancer cells themselves, changes in immune cells, or changes in the environment surrounding the tumour.
1. Cancer Cells Can Become Less Visible to the Immune System
For an immune response to work, immune cells need to recognise cancer as abnormal. Some tumours can acquire changes that make them harder for immune cells to identify or attack.
Changes affecting how cancer cells present tumour-related proteins to T cells can interfere with this process. If the immune system can no longer recognise the cancer effectively, simply releasing an immune checkpoint may not be enough to restore tumour control.
2. The Tumour May Create an Immune-Suppressive Environment
A tumour is not made up only of cancer cells. It also contains blood vessels, connective tissue, immune cells and other cells that interact with the cancer.
Some tumours alter this surrounding environment in ways that suppress immune activity. Certain cells within the tumour microenvironment can interfere with T-cell function or make it more difficult for immune cells to reach the cancer.
*AI-generated image - for illustration only. Clinical accuracy is not guaranteed.
This is one reason why blocking a single immune checkpoint may not always be sufficient. The tumour can use several different mechanisms to protect itself from immune attack.
3. T Cells Can Become Exhausted
T cells are important cancer-fighting immune cells. When they are exposed to persistent stimulation over a long period, such as during ongoing cancer growth, their ability to function effectively can decline. This state is commonly referred to as T-cell exhaustion.
Exhausted T cells may show increased levels of certain checkpoint proteins and have reduced ability to kill tumour cells. Checkpoint inhibitors can restore some aspects of T-cell activity, but they may not completely overcome all forms of T-cell dysfunction.
4. Cancer Cells Can Develop New Genetic Changes
Cancer cells are constantly changing. During treatment, genetic changes may emerge that help some cancer cells survive immune attack.
For example, alterations in genes involved in immune recognition or immune signalling can potentially make tumour cells less vulnerable to T-cell attack. These changes may be present before treatment or develop as the cancer evolves.
This helps explain why a treatment can work for a period of time and then lose effectiveness. The cancer being treated later may no longer be biologically identical to the cancer present when treatment began.
5. Different Parts of the Tumour May Behave Differently
Cancer is often heterogeneous, meaning that not every cancer cell has exactly the same characteristics. One group of cells may be sensitive to immunotherapy while another group is less responsive.
When treatment eliminates the sensitive cells, resistant populations may survive and continue growing. This can contribute to the development of acquired resistance.
What Is the Difference Between Cancer Progression and Immunotherapy Resistance?
Cancer appearing larger on a scan does not always mean that immunotherapy has immediately failed. In some patients receiving immunotherapy, immune cells can enter a tumour and temporarily make it appear larger on imaging.
*AI-generated image - for illustration only. Clinical accuracy is not guaranteed.
This phenomenon is sometimes referred to as pseudoprogression. It is relatively uncommon and needs to be distinguished from genuine tumour progression.
Doctors therefore interpret imaging results together with symptoms, examination findings, previous scans and the overall clinical picture.
Depending on the situation, repeat imaging may be useful before concluding that the cancer is truly progressing. At the same time, confirmed progression should not simply be assumed to be pseudoprogression. The distinction requires clinical assessment rather than relying on the scan alone.
What Happens If Cancer Becomes Resistant to Immunotherapy?
Progression during immunotherapy does not mean that treatment options have necessarily run out. The next step depends on the type of cancer, where it has progressed, previous treatments, the patient's overall health and whether there are other treatment options available.
Depending on the situation, doctors may consider:
- Changing to another type of cancer treatment
- Using chemotherapy or targeted therapy when appropriate
- Combining treatments that work through different mechanisms
- Using radiation or other local treatment for selected areas of disease
- Considering another immunotherapy strategy in carefully selected circumstances
- Evaluating eligibility for a clinical trial
*AI-generated image - for illustration only. Clinical accuracy is not guaranteed.
Not every strategy that is being studied to overcome immunotherapy resistance has been proven effective or is available as standard treatment. Many approaches remain under clinical investigation.
Does Immunotherapy Resistance Mean the Cancer Is Untreatable?
No. Resistance to one immunotherapy does not automatically mean that the cancer cannot be treated. Cancer treatment is often adjusted when the disease changes.
Another therapy may be appropriate depending on the cancer's characteristics and previous treatment history. In some cases, local treatment may also be useful even when the overall disease requires a different systemic treatment.
The available options depend heavily on the individual cancer, so treatment decisions after progression need to be made based on the complete clinical picture rather than the term “immunotherapy resistance” alone.
The Bottom Line
Immunotherapy resistance is a complex process, and there is rarely one reason why cancer stops responding. Some tumours are resistant from the beginning, while others initially respond and later adapt through changes in cancer cells, immune cells or the tumour environment.
PD-L1 and other biomarkers can provide useful information, but no single test can predict every case of resistance. When cancer progresses during immunotherapy, doctors look at imaging, symptoms, treatment history and, when appropriate, additional tumour or molecular information before deciding what to do next.
Most importantly, immunotherapy resistance does not automatically mean that no further treatment is possible. Cancer treatment can evolve as the disease changes, and research continues to identify more precise ways to prevent, understand and overcome resistance.
