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Researchers at Dana-Farber Cancer Institute have discovered that in the most common form of small cell lung cancer (SCLC), tumor blood vessels can prevent natural killer (NK) cells from leaving the bloodstream and entering the tumor, even though the cancer cells themselves are vulnerable to immune attack. The team found that activating the STING immune pathway in the tumor’s vascular environment helped NK cells access the tumor and attack SCLC cells, with an even stronger effect when combined with a DLL3-targeted CAR-NK cell therapy.
Why it matters
Small cell lung cancer is an aggressive form of lung cancer that often does not trigger a strong immune response, leaving many tumors with very few immune cells. Understanding why NK cells are unable to reach and attack SCLC tumors, despite the cancer cells’ vulnerability, could lead to new combination immunotherapy strategies to make these treatments more effective for patients.
The details
The researchers used spatial profiling and a ‘tumor-on-a-chip’ model to determine that the tumor vasculature acts as a barrier, physically and biologically restricting NK cells from exiting the bloodstream and entering the tumor. Activating the STING immune pathway in the tumor’s vascular environment helped open this barrier, allowing NK cells to access and attack the cancer cells. This effect was even stronger when combined with a DLL3-targeted CAR-NK cell therapy.
The study was published in Cancer Cell on March 19, 2026.
The players
Dana-Farber Cancer Institute
A comprehensive cancer center located in Boston, Massachusetts that conducts cancer research and provides cancer treatment.
David Barbie
The senior author of the study and the Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute.
Navin R. Mahadevan
The co-lead author of the study and a former member of Barbie’s laboratory, currently an assistant professor at the University of Michigan.
Matteo Campisi
The first author of the study.
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What they’re saying
“Small cell lung cancer has been notoriously difficult to treat with immunotherapy, in part because the immune system often can’t access the tumor.”
— David Barbie, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute
“Our study shows that the blood vessels around these tumors can act as a barrier that keeps natural killer cells out, and that activating STING can help unlock that barrier. This points to a promising combination strategy that could make NK-based and potentially other immunotherapies more effective for the patients who need new options most.”
— David Barbie, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute
“In this form of small cell lung cancer, the immune cells aren’t failing because they can’t kill—the problem is they can’t get in. By activating STING in the tumor’s vascular neighborhood, we found a way to open the vascular gate so NK cells can enter and attack, and that access appears to make targeted CAR-NK therapy work better.”
— Matteo Campisi, First author
What’s next
Future research will focus on improving the durability and persistence of NK-cell therapies, so they continue to function effectively over time. The team is working with the Rizwan Romee lab, which provided the DLL3 CAR-NK cell, to engineer CAR-NK cells that produce IL-12 to enhance proliferation and anti-tumor activity.
The takeaway
This study highlights a promising combination strategy of activating the STING immune pathway and using DLL3-targeted CAR-NK cell therapy to help natural killer cells access and attack small cell lung cancer tumors, which have been notoriously difficult to treat with immunotherapy. Unlocking this vascular barrier could make NK-based and other immunotherapies more effective for patients with this aggressive form of lung cancer.
