Radiation therapy helps overcome resistance to immunotherapy in some cancers

By activating the immune system, radiation therapy makes certain tumors that are resistant to immunotherapy susceptible to treatment, leading to positive outcomes for patients, according to a new study led by scientists at the Bloomberg-Kimmel Institute for Immune Oncology at the Johns Hopkins Kimmel Cancer Center and the Netherlands Cancer Institute.

In a study published in the journal Nature Cancer, scientists took a detailed look at the molecular biology of non-small cell lung cancer to find out what happens at the cellular and molecular level over time when the cancer is treated with either radiation therapy followed by immunotherapy or immunotherapy alone.

They found that radiation therapy combined with immunotherapy induced a systemic antitumor immune response in lung cancer that is not typically responsive to immunotherapy. The combination therapy also showed improved clinical response in patients whose tumors showed signs of resistance to immunotherapy.

Clinically, the results suggest that radiotherapy may help overcome resistance to immunotherapy in some patients.

“For a subset of lung cancers where we typically don’t expect a therapeutic response, radiation therapy may be particularly effective in helping to bypass primary resistance to immunotherapy; this may also apply to acquired resistance,” said senior study author Valsamo (“Elsa”) Anagnostou, MD, PhD, co-director of the Upper Aerial and Digestive Tract Tumors Program, director of the Thoracic Oncology Bioarchives, chief of the Precision Oncology Analytics Group, co-director of the Molecular Oncology Panel, and co-director of the Johns Hopkins University Center for Precision Medicine in Lung Cancer.

Scientists have long sought to better understand why some tumors become resistant to immunotherapy—a treatment strategy that uses the body's own immune system to fight cancer cells—and how to interrupt that resistance.

Radiation therapy has been proposed as a possible way to induce a systemic immune response through a unique phenomenon called the abscopal effect.

Radiation to the primary tumor site typically kills tumor cells and releases their contents into the local microenvironment. Sometimes the immune system recognizes these contents, “learns” the tumor’s molecular fingerprint, and then activates immune cells throughout the body to attack cancer cells in other areas of the tumor that were not targeted by the radiation, including those far from the primary site.

Because of this effect, radiation therapy could potentially improve the effectiveness of immunotherapy against cancer even in areas that were not irradiated. However, little is known about the molecular biology of the abscopal effect or how to predict when and in which patients it will occur.

To study this phenomenon, Anagnostou and her colleagues obtained samples from lung cancer patients at different times throughout their treatment and from different sites in the body, not just the primary tumor.

They collaborated with Willemijn Thielen and Paul Baas from the Netherlands Cancer Institute, who were conducting a phase II clinical trial looking at the effect of radiotherapy followed by immunotherapy, specifically the PD-1 inhibitor pembrolizumab.

With the help of Thielen and Baas, Anagnostou’s team analyzed 293 blood and tumor samples from 72 patients, taken at baseline and three to six weeks after treatment began. Patients in the control group received immunotherapy alone, while the experimental group received radiation therapy followed by immunotherapy.

The team then performed multi-omics analyses on the samples—that is, they combined a variety of “-omics” tools, including genomics, transcriptomics, and various cellular assays, to deeply characterize what was happening to the immune system systemically and in the local microenvironment of tumors that were not directly exposed to radiation.

In particular, the team focused on immunologically “cold” tumors — tumors that typically do not respond to immunotherapy. These tumors can be identified by certain biomarkers: low mutational load, lack of PD-L1 protein expression, or the presence of mutations in the Wnt signaling pathway.

After radiation and immunotherapy, the team found that the “cold” tumors, those far from the radiation site, experienced a significant reorganization of the tumor microenvironment. Anagnostou describes this as a “warming up” of the tumors — a transition from low or absent immune activity to inflamed areas with marked immune activity, including an expansion of new and pre-existing T cell populations.

"Our results highlight how radiation can enhance the systemic antitumor immune response in lung cancer that would be unlikely to respond to immunotherapy alone," said lead study author Justin Huang, who led the multiomics analyses.

“Our work highlights the value of international and interdisciplinary collaboration in translating knowledge of cancer biology to the clinical level.” Huang was awarded the 2025 Paul Ehrlich Research Award in recognition of breakthrough discoveries by young investigators and their supervisors at the Johns Hopkins University School of Medicine.

Working with Kelly Smith, PhD, an associate professor of oncology at the Kimmel Cancer Center and an investigator at the Bloomberg-Kimmel Institute for Immune Oncology, Anagnostou's team focused on patients who had achieved long-term survival with combination radiation and immunotherapy and ran a functional test to see what these patients' T cells were doing in the body.

In cell cultures, they confirmed that T cells expanded in patients receiving radiation and immunotherapy did indeed recognize specific neoantigens associated with mutations in the patients' tumors.

Finally, by tracking patient outcomes in the clinical trial, the team noted that patients with immunologically cold tumors that were “warmed up” by radiation therapy had better treatment outcomes than those who did not receive radiation therapy.

“This was incredibly exciting and really capped off the whole process,” Anagnostou says. “Not only did we document the abscopal effect, but we also linked the immune response to clinical outcomes in tumors that are not typically expected to respond to immunotherapy.”

Using samples from the same patient cohorts, the team is now working to map the body’s response to immunotherapy by detecting circulating tumor DNA (ctDNA) in the blood. The work was presented April 28 at the annual meeting of the American Association for Cancer Research in Chicago.