Mayo Clinic researchers have identified how lung tumors twist a normal immune safeguard into a shield for cancer, helping explain why many patients do not benefit from immunotherapy. The work reveals a promising new drug target that could make these treatments more effective.
A Mayo Clinic team has uncovered a hidden way lung tumors disarm the body’s defenses, helping explain why many patients do not benefit from immunotherapy and revealing a promising new target to boost those treatments.
The study, published in the journal Cancer Immunology Research, shows that lung tumors can hijack a group of immune cells called regulatory T cells and turn them from peacekeepers into protectors of cancer.
Regulatory T cells normally act as a brake on the immune system, preventing it from becoming overactive and damaging healthy tissue. In lung cancer, the Mayo Clinic researchers and their collaborators found that these same cells can be rewired inside tumors to suppress the very immune attack that immunotherapies are designed to unleash.
“What we are seeing is the tumor taking advantage of a normal immune safety mechanism and turning it to its own benefit,” senior author Henrique Borges da Silva, an immunologist at Mayo Clinic in Arizona, said in a news release. “The same cells that normally prevent immune damage are instead protecting the tumor.”
Lung cancer is the leading cause of cancer-related deaths worldwide. Immunotherapy drugs, which help the immune system recognize and attack tumors, have improved survival for some people with advanced disease. But many patients either do not respond or eventually stop responding, and researchers have been racing to understand why.
To probe that question, the team analyzed patient data from non-small cell lung cancer, the most common form of the disease. They focused on regulatory T cells that had infiltrated lung tumors and looked for molecular clues that might explain their behavior.
They found that these regulatory T cells expressed high levels of a receptor called P2RX7. Patients whose tumor-infiltrating regulatory T cells had higher P2RX7 levels tended to have worse survival outcomes.
P2RX7 acts as a sensor for ATP, a molecule that cells use for energy and that is released in large amounts by stressed or dying cells. Tumors are often packed with ATP, creating a chemical environment that can shape how immune cells behave.
In this study, when regulatory T cells detected ATP through P2RX7, they accumulated inside lung tumors and became more effective at shutting down other immune cells that would otherwise attack the cancer. Instead of helping the body, they helped the tumor.
The researchers then asked what would happen if they removed P2RX7 from regulatory T cells. In experimental models, lung tumors grew more slowly when regulatory T cells lacked this receptor. Without P2RX7, the suppressive grip on the immune system loosened.
Immune cells that specialize in killing cancer were able to move into tumors more easily and were more active once they got there. The team also found that P2RX7 helps regulatory T cells produce CTLA-4, a molecule known for dampening immune responses. Without P2RX7, regulatory T cells were less capable of shutting down immune activity inside lung tumors.
Blocking P2RX7 had another important effect: it improved cooperation between immune cells and B cells, the cells that make antibodies. That shift led to higher levels of antibodies targeting the tumor and to the formation of organized clusters of immune cells inside the cancer. These structures, sometimes called tertiary lymphoid structures, have been linked in other research to better outcomes in lung cancer.
Taken together, the findings suggest that P2RX7 is a key switch that helps turn regulatory T cells into powerful allies of the tumor. By flipping that switch off, it may be possible to weaken the tumor’s defenses and give immunotherapy a better chance to work.
“If we want immunotherapy to reach more patients, we have to understand why it fails,” Borges da Silva added. “This study identifies one of the mechanisms standing in the way.”
To explore how this insight might translate into treatment, the researchers tested a drug that inhibits P2RX7. In their models, the inhibitor led to smaller lung tumors and fewer regulatory T cells inside the tumor environment.
The drug is not yet approved for cancer treatment, and the researchers emphasize that more studies are needed before the approach can be tested in patients. Future work will need to determine how best to combine P2RX7 inhibitors with existing immunotherapies, which patients are most likely to benefit, and whether blocking this pathway has side effects on normal immune function.
Even so, the study adds to a growing body of evidence that targeting immune suppression inside tumors could be as important as stimulating immune attack. By disarming the cells that shield cancer, doctors may be able to extend the benefits of immunotherapy to many more people with lung cancer.
The research underscores a broader shift in cancer treatment: rather than focusing only on killing tumor cells directly, scientists are increasingly trying to re-engineer the tumor’s ecosystem. For patients and families facing lung cancer, discoveries like this one offer a glimpse of more precise, more powerful therapies on the horizon.
Source: Mayo Clinic