PD-L1 (programmed death-ligand 1) is a protein found on the surface of many cells in your body, including some cancer cells. Its normal job is to tell your immune system to stand down, preventing it from attacking healthy tissue. But cancer cells can exploit this protein, using it like a shield to hide from immune cells that would otherwise destroy them. Understanding PD-L1 matters because it has become one of the most important markers in modern cancer treatment, helping doctors decide whether a type of immunotherapy might work for you.
How PD-L1 Works in a Healthy Body
Your immune system has a built-in braking system to keep it from going overboard. PD-L1 is part of that system. It works by connecting with a receptor called PD-1, which sits on the surface of T cells (the immune cells responsible for finding and killing threats). When PD-L1 locks onto PD-1, it sends a “don’t attack” signal. The T cell’s ability to kill is suppressed, it stops multiplying, and it produces fewer of the chemical signals that rally other immune cells.
This is essential. Without this brake, your immune system would attack your own organs, joints, and tissues. PD-L1 appears on many normal cells throughout the body precisely to prevent that kind of autoimmune damage.
How Cancer Cells Exploit PD-L1
Cancer cells are, at their core, your own cells gone rogue. Your immune system can often recognize and kill them. But many tumors have found a workaround: they ramp up PD-L1 production on their surface. By displaying large amounts of this protein, tumor cells essentially disguise themselves as normal tissue. When a T cell approaches a PD-L1-coated cancer cell, it receives the “don’t attack” signal and backs off.
Research published in The Journal of Experimental Medicine demonstrated that PD-L1 on tumor cells acts as a “molecular shield,” directly reducing the killing ability of the immune cells that infiltrate the tumor. Crucially, this protection is selective. Cancer cells with PD-L1 on their surface survive, while those without it in the same tumor can still be destroyed. This gives PD-L1-positive cancer cells a growth advantage, allowing the tumor to expand while the immune system is held at bay.
PD-L1 as a Cancer Biomarker
Doctors now routinely test tumors for PD-L1 levels to help guide treatment decisions. The test is performed on a tissue sample, either from a biopsy or from surgery to remove the tumor. If you’ve already had a biopsy to diagnose your cancer, that same tissue sample can often be used.
PD-L1 expression is measured as a percentage, from 0% to 100%, based on how many tumor cells in the sample show the protein on their surface. Two scoring methods are commonly used:
- Tumor Proportion Score (TPS): Measures PD-L1 only on tumor cells. This is the standard approach for lung cancer.
- Combined Positive Score (CPS): Counts PD-L1 on both tumor cells and nearby immune cells. This method is used for cancers like stomach cancer and head and neck cancer, where including immune cells in the count better predicts how well treatment will work.
Tumors are typically grouped into three categories: less than 1% (low or negative), 1% to 49% (intermediate), and 50% or greater (high). These thresholds matter because they directly influence treatment options.
Why PD-L1 Levels Affect Treatment Decisions
A class of drugs called checkpoint inhibitors works by blocking the connection between PD-1 and PD-L1. By preventing this handshake, the drugs release the brakes on T cells, allowing them to recognize and attack tumor cells again.
The higher a tumor’s PD-L1 level, the more likely these drugs are to work as a first treatment. A meta-analysis of advanced lung cancer trials found that patients with PD-L1 of 50% or greater who received a checkpoint inhibitor had a response rate of about 40%, compared to 29% for standard chemotherapy. Those patients also had better long-term survival at two and three years.
For patients with intermediate PD-L1 levels (1% to 49%), checkpoint inhibitors alone produced a lower initial response rate of about 17%, but still showed improved two-year survival over chemotherapy. Patients with PD-L1 below 1% had the lowest response rate at roughly 8%, and outcomes were generally no better than chemotherapy when checkpoint inhibitors were used alone. For patients who had already tried other treatments, however, checkpoint inhibitors performed similarly to or better than chemotherapy across all PD-L1 levels.
These numbers explain why PD-L1 testing is so central to treatment planning. A high score can mean the difference between starting with immunotherapy alone versus combining it with chemotherapy, or using a different approach entirely.
Checkpoint Inhibitor Drugs That Target This Pathway
Several FDA-approved drugs block the PD-1/PD-L1 pathway. Some attach to PD-1 on the T cell side (pembrolizumab, nivolumab, cemiplimab), while others attach to PD-L1 on the tumor side (atezolizumab, avelumab, durvalumab). The end result is the same: the “don’t attack” signal is blocked, and the immune system reactivates against the cancer.
These drugs are approved for use in a wide range of cancers, including lung cancer, melanoma, bladder cancer, kidney cancer, head and neck cancers, and others. Which drug is used depends on the cancer type, its PD-L1 level, and whether the patient has received prior treatment.
Side Effects of Blocking PD-L1
Because these drugs work by releasing the immune system’s brakes, the most common side effects happen when the immune system starts attacking healthy tissue. These are called immune-related adverse events, and they differ from the side effects of traditional chemotherapy.
Skin reactions like rash, itching, and vitiligo (patches of lightened skin) are among the earliest side effects, typically appearing within the first one to twelve weeks of treatment. Diarrhea occurs in about 20% of patients on PD-1 inhibitors, though actual colitis (inflammation of the colon) is much rarer at around 1%. Thyroid problems are relatively common: hypothyroidism develops in 8% to 14% of patients taking pembrolizumab. Joint pain affects about 8% of patients across checkpoint inhibitor trials.
Lung inflammation, called pneumonitis, is uncommon (1% to 3% of patients on PD-1 or PD-L1 inhibitors) but is taken seriously because it can be dangerous if not caught early. Overall, severe side effects occur in about 10% of patients on PD-1 inhibitors, a significantly lower rate than the 31% seen with older checkpoint inhibitors that target a different receptor called CTLA-4. Most immune-related side effects are mild and manageable, but they require monitoring throughout treatment because they can affect almost any organ system.