Checkpoint Inhibitors: How They Unleash Your Immune System Against Cancer

---

Checkpoint Inhibitors: How They Unleash Your Immune System Against Cancer

By Peter Teoh, Science Writer

Checkpoint inhibitors are drugs that “take the brakes off” immune cells so they can better see and attack cancer, and they are now a standard option for many advanced or metastatic cancers. They do not work for everyone, but in some patients they can shrink tumors for years and significantly extend survival. pmc.ncbi.nlm.nih

How checkpoint inhibitors work

Immune checkpoints are proteins on immune cells (mainly T cells) that act like brakes to prevent over-activation and autoimmunity. Two of the best-known checkpoints are: pmc.ncbi.nlm.nih

• CTLA-4: controls early T-cell activation in lymph nodes, dampening “priming” of new anti-tumor T cells. pmc.ncbi.nlm.nih
• PD-1 / PD-L1: controls already-activated T cells out in tissues and tumors, making them “exhausted” so they stop killing cancer cells. spandidos-publications

Many tumors exploit these pathways by expressing ligands such as PD-L1, which binds PD-1 on T cells and switches them off, allowing the cancer to grow unchecked. Checkpoint inhibitor drugs are monoclonal antibodies that block CTLA-4, PD-1, or PD-L1, restoring T-cell activity, cytokine production, and direct killing of cancer cells. pmc.ncbi.nlm.nih

Common examples include ipilimumab (CTLA-4), nivolumab and pembrolizumab (PD-1), and atezolizumab and durvalumab (PD-L1). cancerresearchuk

Use in advanced and metastatic cancer

Checkpoint inhibitors have transformed the treatment of several advanced cancers, where cure with chemotherapy or radiation alone was rarely possible. They are now routinely used in: mdanderson

• Advanced melanoma
• Non-small cell lung cancer
• Kidney (renal cell) cancer
• Bladder cancer
• Certain breast cancers
• Head-and-neck, liver, colorectal (with specific mutations), and others pmc.ncbi.nlm.nih

In diseases like metastatic melanoma, drugs such as ipilimumab, nivolumab, and pembrolizumab have significantly improved median overall survival and long-term remission rates compared with older chemotherapies. Similar benefits (longer progression-free survival and overall survival) have been seen in advanced lung cancer and some other solid tumors. pmc.ncbi.nlm.nih

Ways they are used in advanced cancer

Depending on the cancer type and stage, checkpoint inhibitors may be used:

• As first-line therapy for metastatic disease (for example, PD-1 or PD-L1 inhibitors in advanced lung cancer or melanoma). pmc.ncbi.nlm.nih
• Together with chemotherapy to improve response rates and survival versus chemotherapy alone. ascopubs
• In combination with targeted therapies (e.g., MAPK inhibitors in BRAF-mutant melanoma) to exploit synergistic immune and tumor-cell effects. pmc.ncbi.nlm.nih
• As adjuvant therapy after surgery in high-risk cancers to reduce recurrence. pmc.ncbi.nlm.nih

Combination and dual checkpoint blockade

Sometimes blocking one checkpoint is not enough because tumors use multiple suppressive mechanisms. Combining CTLA-4 and PD-1 inhibitors can broaden and deepen T-cell responses: CTLA-4 blockade expands new tumor-specific T-cell clones, while PD-1 blockade keeps them active within the tumor. frontiersin

In metastatic melanoma, dual therapy (e.g., ipilimumab plus nivolumab) has produced higher response rates and improved survival versus either drug alone, though at the cost of more side effects. Similar combination strategies are being tested or used in other advanced cancers, often along with chemotherapy or targeted agents. pnas

Limitations, biomarkers, and side effects

Not all advanced cancers respond, and even in responsive cancers only a fraction of patients achieve durable benefit. Researchers use biomarkers such as PD-L1 expression, tumor mutational burden, and specific genetic features to predict who is more likely to respond, but these tests are imperfect. Resistance can arise through changes in tumor antigens, loss of antigen presentation, or recruitment of suppressive immune cells. pmc.ncbi.nlm.nih

Because these drugs release immune brakes, they can cause immune-related side effects where the immune system attacks normal organs, leading to colitis, hepatitis, pneumonitis, skin rash, endocrine problems, and others. These are often manageable with steroids or other immunosuppressants, but in severe cases treatment must be stopped. spandidos-publications

How this applies practically in advanced cancer

For a person with advanced cancer, clinicians typically:

• Confirm if their cancer type and stage has evidence-based indications for a checkpoint inhibitor.
• Check biomarkers (e.g., PD-L1) and overall health to decide between single-agent, combination, or adding chemo/targeted therapy.
• Monitor closely for early signs of immune-related side effects and tumor response using scans and lab tests. mdanderson