Immune Checkpoint Inhibitors: How Do They Treat Cancer?

Immune checkpoint inhibitors are a type of cancer immunotherapy that helps the immune system attack cancer cells. They work by blocking specific proteins that normally keep immune responses under control. When these “brakes” are blocked, certain immune cells, particularly T cells, may remain active against cancer.

This approach is different from treatments that primarily act directly on cancer cells. Instead, immune checkpoint inhibitors change the way the immune system interacts with the tumor. 

To understand where checkpoint inhibitors fit within cancer treatment, you can also explore our Cancer Immunotherapy page for a broader overview.

What Are Immune Checkpoints?

Your immune system needs to be carefully controlled. It must be strong enough to recognize and destroy harmful or abnormal cells, but it also needs mechanisms that prevent it from attacking healthy tissues unnecessarily.

Immune checkpoints are part of this natural control system. They involve proteins on immune cells and, in some cases, other cells that send signals to regulate immune activity.

One important group of immune cells involved in this process is T cells. When checkpoint pathways are activated, they can reduce T-cell activity and prevent excessive immune responses.

This protective mechanism can become a problem in cancer. Some tumors can use checkpoint pathways to reduce the immune response against them, making it harder for T cells to destroy the cancer cells.

How Do Cancer Cells Evade the Immune System?

Cancer cells are abnormal, but they develop from the body's own cells. This can make it difficult for the immune system to distinguish them from healthy tissue.

Some cancer cells also develop mechanisms that help them avoid immune attack. One of the best-known mechanisms involves the PD-1 and PD-L1 pathway.

PD-1 is a protein found on T cells. PD-L1 can be found on some normal cells and is present at higher levels on certain cancer cells. When PD-L1 binds to PD-1, it can reduce the ability of the T cell to attack the cell carrying the signal. In effect, the interaction can act like a signal telling the immune cell to slow down or stop its attack.

How Do Immune Checkpoint Inhibitors Work?

 When a checkpoint pathway such as PD-1/PD-L1 is blocked, the inhibitory signal is reduced. This can allow T cells to remain active and improve their ability to recognize and attack cancer cells.

A simplified way to understand the process is:

1. The immune system recognizes abnormal features associated with cancer.
2. T cells become involved in the response against the tumor.
3. The cancer uses an immune checkpoint pathway to reduce T-cell activity.
4. A checkpoint inhibitor blocks that inhibitory pathway.
5. The T cells can remain active against the cancer.
6. The activated immune response may then damage or destroy cancer cells.

Checkpoint inhibitors therefore do not simply “boost immunity” throughout the body. They target specific mechanisms that can suppress the immune response against cancer.

What Are PD-1 and PD-L1 Inhibitors?

PD-1 and PD-L1 inhibitors target different parts of the same immune checkpoint pathway.

PD-1 inhibitors

PD-1 is found on T cells. When it binds to PD-L1, T-cell activity can be reduced. PD-1 inhibitors block the PD-1 protein, preventing this interaction from sending its usual inhibitory signal.

PD-L1 inhibitors

PD-L1 may be present on cancer cells and other cells. PD-L1 inhibitors block this protein, making it more difficult for PD-L1 to bind to PD-1 on T cells. Although both approaches affect the PD-1/PD-L1 pathway, they act at different points within it.

What Is CTLA-4?

CTLA-4 is another immune checkpoint protein found on T cells. It helps regulate T-cell activation and prevents immune responses from becoming excessive.

Some immune checkpoint inhibitors block CTLA-4. When this pathway is inhibited, T-cell activity can increase, potentially strengthening the immune response against cancer.

CTLA-4 and PD-1/PD-L1 are different checkpoint pathways. Because they regulate immune activity through different mechanisms, certain treatment plans may use inhibitors targeting more than one checkpoint.

Why Are There Different Types of Checkpoint Inhibitors?

Cancer is not a single disease, and tumors can interact with the immune system in different ways. Different checkpoint inhibitors have therefore been developed to target different immune-regulatory pathways.

The main checkpoint targets used in cancer treatment include:

• PD-1 – a checkpoint protein found on T cells
• PD-L1 – a protein that can be present on cancer cells and other cells
• CTLA-4 – a checkpoint protein involved in regulating T-cell activation

Other immune checkpoint targets are also being investigated, and some have entered clinical use in specific treatment settings.

Which Cancers Can Be Treated With Checkpoint Inhibitors?

Immune checkpoint inhibitors are used in the treatment of several types of cancer. Their use depends on the particular medicine, cancer type, stage, tumor characteristics, previous treatment, and other clinical factors.

Checkpoint inhibitors may be used in certain patients with cancers such as:

• Melanoma
• Lung cancer
• Kidney cancer
• Bladder and other urothelial cancers
• Head and neck cancers
• Hodgkin lymphoma
• Liver cancer
• Stomach and gastroesophageal cancers
• Colorectal cancer
• Cervical cancer
• Certain breast cancers
• Some other cancers with particular molecular or biomarker characteristics

Why Is Biomarker Testing Important?

In some cancers, testing the tumor can provide information that helps doctors determine whether a checkpoint inhibitor may be appropriate.

One commonly used biomarker is PD-L1 expression. Testing can measure PD-L1 in the tumor or surrounding cells, depending on the cancer and the test being used. In certain treatment settings, the result can help guide treatment decisions.

Other biomarkers can also be relevant. For example, some tumors have microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). These characteristics can be important when determining eligibility for particular immunotherapy treatments.

Biomarker testing is not the same for every cancer. The tests considered depend on the type of cancer and the treatment being evaluated.

Can Checkpoint Inhibitors Be Combined With Other Cancer Treatments?

Yes. Depending on the cancer and treatment setting, an immune checkpoint inhibitor may be used alone or together with another treatment. Possible combinations include:

• Two different checkpoint inhibitors
• Immunotherapy and chemotherapy
• Immunotherapy and targeted therapy
• Immunotherapy with other cancer treatments

The purpose of combining treatments is to use different mechanisms to attack or control the cancer. However, combination treatment can also change the potential side-effect profile, so the benefits and risks need to be considered carefully for each patient.

How Is the Response to Immunotherapy Monitored?

Doctors generally assess the response to treatment using a combination of imaging, physical examination, symptoms, laboratory tests, and other investigations when appropriate.

Assessing immunotherapy response can sometimes be different from assessing treatments that directly affect tumor growth. Changes seen on imaging need to be interpreted in the context of the patient's overall clinical picture.

Doctors therefore consider more than one factor when deciding whether treatment is working, whether it should continue, or whether the treatment plan needs to change.

What Side Effects Can Checkpoint Inhibitors Cause?

Checkpoint inhibitors work by changing immune activity. Because of this, the immune system can sometimes become active against healthy tissues as well as cancer cells.

Common side effects can include:

• Fatigue
• Skin rash
• Itching
• Diarrhea
• Changes in thyroid function

More significant immune-related reactions can cause inflammation in different organs. Depending on the affected organ, this may involve the lungs, liver, bowel, kidneys, heart, pancreas, thyroid, pituitary gland, skin, or nervous system.

Are Immune Checkpoint Inhibitors the Same as Chemotherapy?

No. They work through different mechanisms. Chemotherapy uses medicines that directly affect cells through mechanisms that can damage or prevent the growth of cancer cells. 

Immune checkpoint inhibitors primarily work by interfering with immune-regulatory pathways so that T cells can respond more effectively against cancer. Because their mechanisms are different, immunotherapy and chemotherapy can sometimes be used together.

The Bottom Line

Immune checkpoint inhibitors treat cancer by interfering with the immune system's natural inhibitory signals. By blocking pathways such as PD-1, PD-L1, or CTLA-4, these medicines can help T cells remain active and attack cancer cells.

However, checkpoint inhibitors do not work in the same way for every cancer or every patient. Tumor characteristics, biomarkers, cancer stage, previous treatment, and other clinical factors can influence whether a particular immunotherapy is appropriate.

Understanding the checkpoint mechanism also explains why these medicines can cause immune-related side effects: the same immune response that helps attack cancer can sometimes affect healthy tissues. For this reason, treatment selection and monitoring are important parts of immunotherapy care.