Radiation Therapy Primes “Cold” Lung Tumors for Immunotherapy in Landmark Study
A new study reveals that radiation therapy can help overcome resistance to immunotherapy in patients with non-small cell lung cancer, offering renewed hope for those with so-called “cold” tumors that typically don’t respond to immune-based treatments.
Researchers from Johns Hopkins Kimmel Cancer Center and the Netherlands Cancer Institute found that radiation, when used ahead of immunotherapy, stimulates the immune system to recognize and attack tumors more effectively—even those previously considered resistant. Their findings were published July 22 in Nature Cancer and supported by the National Institutes of Health.
“Radiation may be particularly effective to help circumvent primary resistance to immunotherapy,” said senior author Valsamo “Elsa” Anagnostou, MD, PhD, co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “This could potentially be applicable to acquired resistance, too.”
The research builds on the concept of the abscopal effect, a phenomenon in which localized radiation triggers an immune response that extends systemically, attacking cancer at sites far from the original radiation field. While this effect has been observed clinically, the biology behind it remained unclear—until now.
Anagnostou and her team, in collaboration with Dutch researchers Willemijn Theelen and Paul Baas, analyzed 293 tumor and blood samples from 72 patients enrolled in a phase II trial. Participants received either pembrolizumab alone—a PD-1 checkpoint inhibitor—or radiation followed by the drug. The team then performed multiomic analyses, combining genomics, transcriptomics, and immune cell profiling to trace the immune response across time and sites in the body.
The study focused on immunologically cold tumors, which often show no expression of the PD-L1 protein, carry low mutation burdens, or have mutations in the Wnt signaling pathway—traits associated with poor immunotherapy response. After radiation, these tumors “warmed up,” showing increased T-cell activity and signs of systemic immune engagement.
“Our findings highlight how radiation can bolster the systemic anti-tumor immune response in lung cancers unlikely to respond to immunotherapy alone,” said lead author Justin Huang. “It underscores the value of international, interdisciplinary collaboration in translating cancer biology insights to clinical relevance.” Huang recently received the 2025 Paul Ehrlich Research Award for his contributions.
Using cell culture tests, the researchers confirmed that the T cells activated by radiation-immunotherapy combinations were targeting tumor-specific neoantigens. Clinically, these patients showed better outcomes than those who received immunotherapy alone.
“It was super exciting, and truly made everything come full circle,” said Anagnostou. “We not only captured the abscopal effect, but we linked the immune response with clinical outcomes in tumors where one would not expect to see immunotherapy responses.”
The team is now extending its work to track circulating tumor DNA (ctDNA) in blood to monitor patient response. That research was presented in April at the American Association for Cancer Research meeting.
This study could help personalize cancer treatment by identifying patients with resistant tumors who may benefit from pre-immunotherapy radiation. While further trials are needed, the results suggest a powerful new role for radiation in the era of immunotherapy.