Checkpoint inhibitors are a type of cancer therapy that work by unleashing the immune system to attack cancer cells more effectively. Normally, the immune system has built-in “checkpoints” — molecules on immune cells that act like brakes to prevent the immune system from attacking the body’s own tissues excessively. Cancer cells can exploit these checkpoints to hide from immune attack. Checkpoint inhibitors block these brakes, allowing immune cells, especially T cells, to recognize and destroy cancer cells.
To understand checkpoint inhibitors, it helps to know about the immune checkpoints themselves. Two of the most studied checkpoints are PD-1 (programmed cell death protein 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). PD-1 is a receptor found on the surface of immune cells such as T cells, macrophages, and dendritic cells. Its natural ligand, PD-L1, is often expressed on cancer cells and some immune cells. When PD-1 binds to PD-L1, it sends an inhibitory signal that reduces the immune cell’s activity. This mechanism normally helps maintain immune tolerance and prevents autoimmunity, but tumors exploit it to evade immune destruction.
Checkpoint inhibitors targeting PD-1 or PD-L1 block this interaction, preventing the “off” signal and allowing T cells to remain active and attack tumor cells. Similarly, CTLA-4 is another checkpoint receptor on T cells that downregulates immune responses early in T cell activation. Blocking CTLA-4 can enhance T cell activation and proliferation, boosting anti-tumor immunity.
The process of cancer immune evasion involves a phenomenon called T cell exhaustion. When T cells are exposed to persistent tumor antigens, they gradually lose their ability to function effectively. Exhausted T cells express high levels of inhibitory receptors like PD-1, which dampen their activity. Checkpoint inhibitors can reinvigorate these exhausted T cells, restoring their ability to proliferate and kill cancer cells.
Checkpoint inhibitors have transformed cancer treatment by providing durable responses in various cancers, including melanoma, lung cancer, kidney cancer, and others. They are often used alone or in combination with chemotherapy or other immunotherapies to improve outcomes. However, not all patients respond, and researchers are actively studying biomarkers such as PD-L1 expression levels, tumor mutational burden, and immune cell infiltration to predict who will benefit most.
While checkpoint inhibitors can unleash powerful anti-cancer immune responses, they can also cause immune-related side effects because they reduce the immune system’s natural tolerance. These side effects can affect organs like the skin, intestines, liver, and lungs, sometimes requiring immunosuppressive treatment.
Newer checkpoint targets beyond PD-1 and CTLA-4, such as TIGIT, are being explored to further enhance cancer immunotherapy. TIGIT is another inhibitory receptor that suppresses T and natural killer (NK) cell activity, and blocking it may provide additional therapeutic benefit.
In summary, checkpoint inhibitors work by blocking the molecular brakes that tumors use to hide from the immune system. By releasing these brakes, they restore the immune system’s ability to detect and destroy cancer cells, offering a powerful and innovative approach to cancer treatment. The field continues to evolve rapidly with ongoing research into new targets, combination therapies, and predictive biomarkers to maximize patient benefit while managing side effects.