A protein already targeted by FDA-approved cancer drugs may also help the body fight the flu, according to new research from the Jackson Laboratory (JAX).
Published in cell reportthe study found that programmed death ligand 1 (PD-L1), a protein best known for helping tumors evade immune attack, instead helped the immunodeficient mice eliminate influenza-infected lung cells and survive the infection.
This finding challenges long-held assumptions about PD-L1’s role in the immune system. Cancer treatments work by blocking PD-L1 and boosting the immune attack against tumors, and new research suggests that enhancing PD-L1 signaling may help control severe respiratory viral infections, particularly in people with T-cell immunodeficiency, such as those infected with HIV or immunosuppression after chemotherapy.
“This finding suggests that cancer-targeted pathways may also be useful in infectious diseases, but vice versa. Cancer treatments block PD-L1, but in influenza, boosting PD-L1 may strengthen host defenses,” said JAX professor and immunologist Silke Paust, who led the study.
PD-L1 is a protein present on the surface of tumor cells and has traditionally cooperated with PD-1, a protein on immune cells, to suppress immune activity. Scientists have long thought that PD-L1’s only role was to help tumors hide from the immune system by switching off immune cells that attack them. But after the unexpected discovery of PD-L1 in human and mouse lung immune cells, Paust’s team began investigating whether PD-L1 might do more than protect tumor cells from immune attack.
Anticancer drugs block the interaction between PD-L1 and PD-1, enhancing immune-mediated tumor killing. However, in influenza, PD-L1 instead helps protect the host by promoting immune killing of infected cells, independent of PD-1. ”
Silke Paust, JAX Professor, Immunologist
The researchers used mice that lack T and B cells and therefore rely on innate immunity from natural killer (NK) cells, which rapidly kill infected or abnormal cells without prior exposure. NK cells are an important antiviral defense and may be particularly relevant for people with T cell deficiency.
“Most healthy people will not die from influenza if they get sick,” Poust says. “In fact, those at risk of death are the very young, the very old, and certainly the immunocompromised. Immunocompromised influenza patients usually die from severe complications, especially viral and secondary bacterial pneumonia leading to respiratory failure, and sometimes sepsis and multiple organ failure.”
After influenza infection, lung NK cells produced high levels of PD-L1. When Paust and his team treated mice with antibodies that activate PD-L1, the mice lived longer because their natural killer cells were better able to destroy virus-infected cells. Importantly, this increased survival rate did not result in increased lung damage, suggesting that the virus could be better controlled without harmful inflammation.
PD-L1 signaling in NK cells also increased expression of a molecule used to destroy virus-infected cells called tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Analysis of human lung tissue and blood samples from COVID-19 patients showed similar increases in PD-L1 and TRAIL expression in lung NK cells, suggesting that the newly identified mechanism may extend beyond mice.
Next, the researchers will study how PD-L1 behaves in healthy lungs, where the immune system is fully equipped, including T cells and B cells that also carry PD-1.
“We still don’t know how PD-L1 behaves in healthy lungs with a complete immune system,” Paust says. “If we can figure that out, it could help us understand how the lung regulates the immune response to viral infections.”
Similar PD-L1 signaling mechanisms may function in tumors, so if confirmed in additional studies, the findings could inform next-generation cancer immunotherapies. The study may also help explain why treatments targeting PD-L1 and PD-1, which are opposite sides of the same immune checkpoint pathway, do not always have the same effect on cancer patients.
“If PD-L1 is sending signals into cells during influenza infection, it may work in the same way in cancer and other diseases,” Paust said. “That could change the way we think about immune checkpoints, because the role of this molecule may depend on the cells that carry it. In the lungs, PD-L1 may be doing two jobs at once.”
This research was supported by unrestricted funding from the National Institutes of Health and the National Institute of Allergy and Infectious Diseases (R01 AI174590) and the Scripps Research Institute.
Other authors are Kayla Frank of The Scripps Research Institute; Himani Sharma, Efthimios Motakis, and Noushin Noorbakhsh of the Jackson Laboratory; Sean Abeynaik and Tridhu R. Hein of the Scripps Research Institute; Cheryl A. Jones, Scott K. Johnson, and S. Mark Tompkins of the University of Georgia;
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Reference magazines:
Frank, K. others. (2026). PD-L1 is an endogenous switch for natural killer cell-mediated TRAIL-dependent antiviral function. cell report. DOI: 10.1016/j.celrep.2026.116939. https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00017-3
