Mayo Clinic research shows why lung cancer resists immunotherapy

Lung cancer cells are able to take advantage of a person’s immune system, specifically T cells, to protect the tumor, according to new research recently published in Cancer Immunology Research. Researchers from Mayo Clinic have discovered a mechanism that could explain this resistance in patients with non-small cell lung cancer.

“If we want immunotherapy to reach more patients, we have to understand why it fails,” Henrique Borges da Silva, Ph.D., an associate professor and lead author, said in a news release. “This study identifies one of the mechanisms standing in the way.”

Lung cancer is the leading cause of cancer-related deaths in the United States. Lung and bronchus cancers are expected to account for an estimated 229,410 new cases in the United States and nearly 125,000 deaths this year, according to the American Cancer Society’s Cancer Facts & Figures 2026 report. The five-year relative survival rate for lung cancer is 28% overall. For the 28% of patients who are diagnosed and treated early, the five-year survival rate is 65%.

Immunotherapy has improved outcomes for patients with many cancers, but lung cancers can be stubbornly resistant to treatment with immunotherapy. In the lung tumor microenvironment, there is a high release of extracellular ATP (eATP), which can come from dying cells or from activated immune cells. This molecule is sensed by a receptor called P2RX7.

“One of the major challenges limiting the effectiveness of immunotherapy in lung cancer is the accumulation of regulatory T cells (Tregs) inside tumors. These cells suppress the immune system and prevent it from effectively controlling tumor growth,” said Igor Santiago De Carvalho, Ph.D., senior research fellow at the Mayo Clinic and one of the authors of the study.

In the Mayo Clinic study, researchers assessed single-cell RNA sequencing data from 42 samples from patients with non-small cell lung cancer. They also collected five samples from patients during biopsies that were conducted at the Mayo Clinic Hospital between September and October 2025.

Researchers found that regulatory T cells inside lung tumors expressed high levels of P2RX7. P2RX7 allows regulatory T cells to sense ATP, a molecule released by stressed cells and commonly found at high levels inside tumors. When these cells detect ATP, they accumulate within lung tumors and suppress immune cells that would otherwise attack the cancer.

“We found that when P2RX7 signaling is blocked specifically in Tregs, these cells accumulate less in lung tumors and become less capable of suppressing anti-tumor immune responses, resulting in better tumor control,” De Carvalho told Managed Healthcare Executive. “This is associated with a reduction in suppressive molecules such as CTLA-4.”

CTLA-4 is a checkpoint receptor that tumor cells hijack to dampen immune responses. Without P2RX7, these regulatory cells were less effective at shutting down immune activity inside lung tumors.

Mayo Clinic researchers also conducted research in mice given non-small cell lung cancer to determine whether the administration of tamoxifen would inhibit P2RX7. Tamoxifen is a hormone therapy that blocks estrogen. It is used to treat patients with breast cancer.

Researchers found that mice that received tamoxifen had enhanced expression of CD4+ and CD8+ T cells. Blocking P2RX7 helped immune cells work more closely with B cells. This led to higher levels of antibodies that target tumors and to the formation of organized immune cell groups inside tumors.

De Carvalho said that in the future, “we aim to develop approaches that selectively inhibit the eATP–P2RX7 pathway in Tregs and combine this strategy with existing immunotherapies such as anti-PD-1/PD-L1 and anti-CTLA-4 treatments.”

He is transitioning to be an independent principal investigator and establishing his own research program in pulmonary immunology.

“My lab will also investigate how the lung vasculature contributes to the release of eATP and promotes Treg accumulation in lung tumors, especially given the large number of Tregs found within the pulmonary vasculature. We hope that this work will contribute to the development of more effective immunotherapies for lung cancer in the coming years.”