Last Updated on December 2, 2025 by Bilal Hasdemir
Immunotherapy has changed how we fight cancer by using the body’s immune system. But, some cancers don’t respond well to this treatment. This makes it hard to use immunotherapy for all cancers.Cancers not responsive to immunotherapyWhat is Immunotherapy?Â
Immunotherapy works well for many cancers. But, it doesn’t work for all. Finding new ways to treat cancers that don’t respond to immunotherapy is key.
Key Takeaways
- Immunotherapy is not effective for all types of cancers.
- Certain cancers exhibit resistance to immunotherapy.
- Understanding immunotherapy limitations is key for cancer treatment.
- Research is ongoing to overcome immunotherapy resistance.
- Alternative treatment strategies are being developed for non-responsive cancers.
The Promise and Limitations of Immunotherapy
Immunotherapy has changed the way we fight cancer, bringing hope to many. It offers a targeted and less invasive option compared to old treatments.
How Immunotherapy Revolutionized Cancer Treatment
Immunotherapy uses the body’s immune system to fight cancer. It has shown great promise, with treatments like checkpoint inhibitors, adoptive cell therapy, and monoclonal antibodies. These have helped many patients, giving them new hope.
Types of Immunotherapy Approaches
Immunotherapy has different methods, each working in its own way. Checkpoint inhibitors help the immune system attack cancer more easily. Adoptive cell therapy boosts a patient’s immune cells to fight cancer better. Monoclonal antibodies target specific proteins on cancer cells, helping the immune system destroy them.
General Limitations and Challenges
Immunotherapy has its challenges, like cancer immune evasion and tumor microenvironment resistance. Not all patients respond well, and some cancers are harder to treat. It’s important to understand these issues to make better treatments.
The success of immunotherapy can be limited by the tumor’s ability to hide from the immune system. The area around the tumor can also suppress the immune response. Researchers are working on new and combined therapies to improve how well the immune system fights cancer.
Cancers Not Responsive to Immunotherapy
Immunotherapy is a promising treatment, but it faces a big challenge. Many cancers don’t respond to it. Finding out why is key to making treatments better.
Definition of Immunotherapy Resistance
Immunotherapy resistance happens when cancer cells avoid or don’t react well to treatments. This makes it hard to treat cancer effectively.
Primary vs. Acquired Resistance
There are two main types of resistance to immunotherapy. Primary resistance means a cancer never works with the treatment. Acquired resistance is when a cancer starts to work but then stops.
Knowing the difference is important for making treatment plans. Both types involve complex interactions between cancer cells and the immune system.
Factors Determining Response Rates
Several things affect how well a cancer responds to immunotherapy. Two important ones are tumor mutational burden and immune infiltration status.
Tumor Mutational Burden
Tumor mutational burden (TMB) is the number of mutations in a tumor. Cancers with many mutations are more likely to work with immunotherapy. This is because their mutated proteins are seen as foreign by the immune system.
A study in the Journal of Clinical Oncology showed that patients with high TMB tumors do better with checkpoint inhibitors. Those with low TMB tumors don’t do as well.
Immune Infiltration Status
The immune infiltration status of a tumor is how many immune cells are there. Tumors with lots of immune cells tend to do better with immunotherapy.
“The presence of immune cells within the tumor microenvironment is a critical factor in determining the response to immunotherapy.” – A Cancer Immunologist
Here’s a table comparing different cancers based on TMB and immune infiltration status:
| Cancer Type | Tumor Mutational Burden | Immune Infiltration Status | Response to Immunotherapy |
| Melanoma | High | High | High Response Rate |
| Pancreatic Cancer | Low | Low | Low Response Rate |
| Non-Small Cell Lung Cancer | Variable | Variable | Variable Response Rate |
As shown, cancers with high TMB and lots of immune cells do better with immunotherapy. Knowing these factors helps in making treatment plans that work better.
Pancreatic Cancer: A Fortress Against Immunotherapy
Pancreatic cancer is hard to treat with immunotherapy because of its dense stroma. This makes it hard for treatments to reach the cancer cells. The tumor’s environment also works against the treatment.
Dense Stromal Barrier and Immunosuppression
The dense stroma in pancreatic cancer blocks immunotherapy. It stops immune cells from getting to the tumor. It also makes the area around the tumor suppress the immune system.
Here’s what makes pancreatic cancer’s environment so tough:
- Immunosuppressive cells like regulatory T cells and myeloid-derived suppressor cells.
- Immunosuppressive cytokines like TGF-β and IL-10.
- Checkpoint molecules like PD-L1 on tumor cells.
Low Mutational Burden in Pancreatic Adenocarcinoma
Pancreatic adenocarcinoma has a low mutational burden. This makes it hard for immunotherapy to work. Tumors with many mutations can be recognized by the immune system, making them easier to treat.
The low mutational burden in pancreatic adenocarcinoma means fewer targets for immunotherapy. This makes it harder to fight with cancer.
Current Clinical Trials and Combination Approaches
Despite the challenges, researchers are trying new ways to fight pancreatic cancer. They’re looking at combining different treatments. This includes:
- Using checkpoint inhibitors with other treatments or targeted therapies.
- Employing oncolytic viruses to kill tumor cells and boost the immune response.
- Targeting the tumor stroma to help treatments get through better.
These new strategies aim to break through the dense stroma and suppressive environment. They hope to make immunotherapy more effective against pancreatic cancer.
Glioblastoma and Central Nervous System Tumors
Immunotherapy for glioblastoma and other central nervous system tumors is hard because of the blood-brain barrier. This barrier keeps out harmful substances but also stops many treatments from reaching the tumor.
Blood-Brain Barrier Challenges
The blood-brain barrier is a big problem for delivering immunotherapy to glioblastoma patients. Scientists are working on new ways to get treatments past this barrier.
Immunosuppressive Microenvironment in Brain Tumors
The immunosuppressive microenvironment in glioblastoma tumors is another big challenge. This environment weakens the immune system, making it hard for treatments to work. It’s important to understand how this works to find better treatments.
Failed Clinical Trials and Lessons Learned
Many clinical trials have tried to use immunotherapy for glioblastoma, but they haven’t worked well. It’s key to learn from these failures to make future treatments better.
Checkpoint Inhibitor Limitations
Checkpoint inhibitors, a type of immunotherapy, have worked well in some cancers. But they haven’t been as effective in glioblastoma. Scientists are studying why this is to find new ways to help.
CAR-T Cell Therapy Challenges
CAR-T cell therapy is another immunotherapy approach. It modifies T cells to attack cancer cells. But, it faces challenges in glioblastoma, like severe side effects and a complex tumor environment.
Even with these challenges, researchers are hopeful about immunotherapy’s future in glioblastoma. They are working hard in research and clinical trials to find new ways and combinations to help patients.
Prostate Cancer’s Resistance to Checkpoint Inhibitors
Prostate cancer is hard to treat with immunotherapy, like checkpoint inhibitors. This is because of several reasons.
Low Mutational Burden and PD-L1 Expression
One big reason is the low mutational burden in prostate cancer. Tumors with few mutations are harder for the immune system to fight. Also, PD-L1, a target for checkpoint inhibitors, is not always present in prostate cancer. This makes treatment even harder.
Sipuleucel-T: The Exception to Immunotherapy Failure
Sipuleucel-T stands out as a success in treating prostate cancer. It boosts the immune system to attack cancer cells. This shows that some immunotherapies can work against prostate cancer.
Combination Strategies Under Investigation
Scientists are looking into combination strategies to make immunotherapy better for prostate cancer. They’re trying to mix checkpoint inhibitors with other treatments. This could help get past the resistance.
Research into prostate cancer’s resistance and new immunotherapies gives hope. It aims to improve treatment results for those with this tough disease.
Acute Myeloid Leukemia (AML) and Immunotherapy Failure
Despite new treatments, Acute Myeloid Leukemia (AML) is hard to treat with immunotherapy. AML is a blood cancer that many immunotherapies can’t beat.
Unique Challenges in Blood Cancers
Blood cancers like AML are tough for immunotherapy. They spread through the body, making them hard to target. The complex and heterogeneous nature of AML makes treatment even harder. It has many genetic mutations that affect how well it responds to therapy.
“The heterogeneity of AML is a significant barrier to effective immunotherapy,” experts say. This means we need a variety of treatments to tackle it.
Immune Evasion Mechanisms in AML
AML cells find ways to avoid the immune system. They use checkpoint molecules like PD-L1 to stop T-cells from working. They also create a place that suppresses the immune system. The ability of AML cells to evade immune detection is a big reason why immunotherapy often fails.
- Expression of checkpoint molecules (e.g., PD-L1)
- Creation of an immunosuppressive microenvironment
- Evasion of immune detection by AML cells
Promising Approaches Beyond Checkpoint Inhibition
Checkpoint inhibitors haven’t worked well for AML. But, researchers are looking at new ways. Adoptive T-cell therapies and CAR-T cell therapies are showing promise. Also, treatments that target AML’s immune evasion are being studied.
Experts believe, “The future of AML treatment lies in innovative approaches.” This is what researchers are working on to help AML patients.
Colorectal Cancer: A Tale of Two Responses
Colorectal cancer reacts differently to immunotherapy, depending on the type. Some types do better than others. This is because colorectal cancer is very diverse, with many different characteristics.
MSI-High vs. MSS Colorectal Cancers
The tumor’s microsatellite instability (MSI) status is key. MSI-high tumors tend to do better with immunotherapy than microsatellite-stable (MSS) ones. This is because MSI-high tumors have more genetic changes, making them easier for the immune system to attack.
| Tumor Type | Response to Immunotherapy | Mutational Burden |
| MSI-High | High Response Rate | High |
| MSS | Low Response Rate | Low |
Why Most Colorectal Cancers Don’t Respond
Even though immunotherapy works well for MSI-high cancers, most colorectal cancers don’t respond. This is because they have a low mutational burden and an environment that suppresses the immune system.
Strategies to Convert Cold to Hot Tumors
To help MSS colorectal cancers, researchers are looking at new ways to make tumors more active. They want to turn “cold” tumors into “hot” ones. This involves using combination therapies to make tumors more visible to the immune system.
By understanding how different types of colorectal cancer react to treatment, doctors can find better ways to help patients. This is a big step towards improving treatment options for this complex disease.
Mechanisms Behind Immunotherapy Resistance
Understanding why immunotherapy doesn’t always work is key to better cancer treatments. Immunotherapy has changed cancer treatment, giving hope to many. But, tumors can fight off the immune system’s attacks.
Tumor Microenvironment and Immune Suppression
The tumor microenvironment (TME) is vital in fighting off immunotherapy. It’s a mix of cancer cells, immune cells, and more, all working together. They use signals to communicate.
Immunosuppressive Cell Populations
Cells like Tregs and MDSCs in the TME help tumors hide from the immune system. They stop T cells from working well, making immunotherapy less effective.
“The presence of immunosuppressive cells in the tumor microenvironment is a major obstacle to effective immunotherapy.”
Cytokine and Chemokine Influences
Cytokines and chemokines are like messengers in the TME. Some, like TGF-β, help tumors hide. Others, like IFN-γ, help the immune system fight cancer.
Immune-Cold and Immune-Desert Tumors
Some tumors don’t have many immune cells, making them hard to treat with immunotherapy. Researchers are looking for ways to make these tumors more responsive.
- Enhancing antigen presentation
- Increasing immune cell infiltration
- Activating anti-tumor immune responses
Checkpoint Inhibitor Resistance Pathways
Checkpoint inhibitors target immune system brakes like PD-1 and CTLA-4. But, tumors can find ways to resist these treatments. This includes making more immune brakes or hiding their antigens.
| Mechanism | Description | Potential Solution |
| Upregulation of alternative checkpoint molecules | Increased expression of other immune checkpoints | Combination therapy targeting multiple checkpoints |
| Loss of tumor antigen expression | Reduced expression of tumor antigens | Enhancing antigen presentation |
Conclusion: Overcoming the Barriers to Immunotherapy Response
Immunotherapy has changed how we fight cancer, but some cancers don’t respond well. It’s key to understand why this happens to find ways to beat these barriers.
Researchers are working hard to make immunotherapy work better. They’re looking into new ways to help patients with cancers that don’t react to treatment. Their goal is to make immunotherapy help more people with cancer.
To make immunotherapy more effective, scientists are trying different approaches. They’re combining treatments and focusing on specific ways cancer can resist. As they learn more, new treatments will likely be developed, giving hope to those with resistant cancers.
By making immunotherapy better, we can help more people with cancer. This could lead to better outcomes and save lives. It’s a hopeful future for cancer treatment.
FAQ
What are the main reasons why some cancers do not respond to immunotherapy?
Cancers may not respond to immunotherapy for several reasons. These include immune evasion by cancer cells, low genetic changes in tumors, and a tumor environment that suppresses the immune system. These factors can limit how well immunotherapy works.
Which types of cancer are typically resistant to immunotherapy?
Certain cancers, like pancreatic, glioblastoma, and prostate cancer, often don’t respond well to immunotherapy. This includes treatments like checkpoint inhibitors.
What is the difference between primary and acquired resistance to immunotherapy?
Primary resistance means a cancer never responds to immunotherapy. Acquired resistance happens when a cancer first responds but then stops working with the treatment.
How does the tumor microenvironment affect immunotherapy response?
The environment around a tumor can greatly affect how well immunotherapy works. It can do this by using immune suppression through different cells and signals.
Are there any immunotherapies that have shown efficacy in prostate cancer?
Yes, sipuleucel-T has shown to work in prostate cancer. It helps the immune system fight prostate cancer cells.
What are researchers doing to overcome immunotherapy resistance in colorectal cancer?
Researchers are trying to make “cold” tumors “hot” to improve immunotherapy in colorectal cancer. This is important for MSS tumors.
Why is pancreatic cancer difficult to treat with immunotherapy?
Pancreatic cancer is hard to treat with immunotherapy. This is because of its dense tissue, immune suppression, and low genetic changes.
What challenges does the blood-brain barrier pose for immunotherapy in glioblastoma?
The blood-brain barrier makes it hard to get immunotherapy to glioblastoma. This makes treatment more complicated.
Are there alternative approaches being explored for AML immunotherapy?
Yes, researchers are looking into new ways to treat AML. This is because current treatments have their limits.
How do MSI-high and MSS colorectal cancers differ in their response to immunotherapy?
MSI-high colorectal cancers usually respond better to immunotherapy. MSS tumors, on the other hand, often don’t respond as well.
References
ScienceDirect. Evidence-Based Medical Insight. Retrieved from https://www.sciencedirect.com/science/article/pii/S009286742200003X
