General practitioner examining a patient’s hand for signs of rheumatoid arthritis.
A breakthrough in cancer therapy could open a whole new frontier in medicine. Scientists are now exploring an exciting possibility: using natural checkpoints in the immune system to treat autoimmune diseases such as lupus, rheumatoid arthritis and type 1 diabetes. While checkpoints are targeted in cancer immunotherapies, this unexpected change could revolutionize also how we treat these chronic conditions, giving hope that a therapy built to fight cancer could also calm an overworked immune system.
Checkpoints and cancer
What are checkpoints and what do they do? To understand their value, let’s turn to our body’s defense system: the immune system.
The immune system constantly scans the body for threats such as viruses, bacteria or cancer cells. But like any sound security system, its activity must be carefully controlled. If it is too active, the immune system can damage healthy cells; if it is too inactive, it will not recognize the dangers lurking nearby.
Checkpoints help maintain this delicate balance. These proteins are found on the surface of immune cells and can tell the immune system to speed up or slow down. Many, but not all, checkpoints function as built-in brakes that prevent immune cells from reacting and attacking healthy tissue.
But cancer complicates things. Cancer cells cleverly hijack these brakes and trick the immune system into slowing down. These disabled immune cells no longer detect cancer cells that are growing out of control.
This is where checkpoint inhibitors come in. This new class of cancer immunotherapies puts these checkpoints in place. Each infusion contains antibodies that block checkpoint proteins like a hand on a light switch, preventing cancer cells from turning off the immune system. This allows your immune cells to recognize and attack the cancer cells they had missed. Instead of directly affecting cancer cells, these inhibitors empower the immune system to do what it is naturally designed to do: fight threats and protect your body. This breakthrough approach has become an invaluable therapy for several advanced forms of cancer, including melanoma and Hodgkin lymphoma.
Flipping the script on autoimmunity
How can people with autoimmunity benefit from checkpoint inhibitors, a drug that traditionally stimulates the immune system? Autoimmune diseases arise when overactive immune cells mistakenly attack the body’s tissues, leading to inflammation and damage. For these patients, more immune activity would only make their condition worse. In fact, most people with autoimmune disorders rely on immunosuppressive drugs to calm their immune system.
What if we flipped the script? What if we used checkpoints SILENCE the immune system instead of feeding it? This reverse strategy could unlock new ways to treat autoimmune diseases with therapies that, until now, have been largely reserved for cancer.
There are two possible ways to pursue this goal. The first is to use stimulating points to suppress the immune system. An example of a strategy already in use is a drug called Abatacept, which taps into the immune-modulating power of checkpoints. Abatacept reduces immune activity by increasing the activity of CTLA-4, a checkpoint receptor that decreases T-cell activation. By turning off immune responses through this mechanism, Abatacept helps reduce swelling and joint damage in people with autoimmune arthritis. It has proven particularly valuable for patients who do not respond to other treatments. Interestingly, CTLA-4’s role in autoimmune treatment contrasts with its use in cancer therapies, where blocking the same checkpoint encourages immune cells to attack tumors more aggressively.
Agonists, drugs that mimic natural proteins, may achieve a similar effect with further exploration. These therapies can mimic checkpoint proteins and reduce excessive immune activity. In a preclinical study, NYU researchers suggest that activation an immune checkpoint called PD-1 can restore balance to the immune system, particularly through strengthening mechanisms involving how the receptor forms pairs (or dimers). Interestingly, PD-1 is usually blocked in cancer treatments to enhance antitumor activity, but in autoimmunity, its activation can help suppress harmful immune activity.
A second possible approach involves creating a new class of checkpoint inhibitors—those that work in reverse. These new therapies would block immune-stimulating checkpoints, preventing them from activating immune cells and therefore reducing harmful immune activity. This is in contrast to existing cancer checkpoint inhibitors, which stop cancer cells from taking over. immuno-suppressant checkpoint proteins. Although still in the early stages, promising candidates include CD137 and CD40, which play roles in immune activation.
Looking Forward
Checkpoint inhibitors, long known for revolutionizing cancer treatment, are now sparking curiosity in a new direction: their potential to mitigate autoimmune diseases. This counterintuitive strategy—silencing the immune system rather than activating it—represents a bold reimagining of these therapies. Although this concept is just beginning to take shape, and we still don’t know the potential complications and limitations these drugs may have, this line of research has exciting potential to reimagine how we approach immune-related conditions.