Radiation may boost response in some immunotherapy resistant lung cancers

Cancer-immune cell interactions. Credit: Katerina Karaindrou x DALL-E Molecular Tumor Board fellow at The Sidney Kimmel Comprehensive Cancer Johns Hopkins Medicine

CANCER DIGEST – Sept. 28, 2025 – Radiation therapy followed by immunotherapy stimulates a systemic anti-tumor response in lung cancers that typically do not respond to immunotherapy alone, a new study shows.

The research led by Justin Huang, a research assistant in the lab of Valsamo “Elsa” Anagnostou, M.D., Ph.D.,at Johns Hopkins Medicine, compared outcomes of patients with non-small cell lung cancer when treated with immunotherapy alone or with radiation followed by immunotherapy. They found that the combination therapy stimulated an anti-tumor response and improved clinical response in patients whose tumors were immunotherapy resistant. The study appears in the July 22, 2025 journal Nature Cancer.

“Our findings highlight how radiation can bolster the systemic anti-tumor immune response in lung cancers unlikely to respond to immunotherapy alone,” Huang said in a press release.

In the clinical study, the researchers analyzed blood and tumor samples from 72 non-small cell lung cancer patients taken before and up to six weeks after treatment. Thirty seven of the patients had received immunotherapy alone and 35 had received immunotherapy after three doses of radiation directed at their primary tumors. 

Using a combination of technical genomic assays the team analyzed the effects on the immune system and local microenvironment surrounding the tumor sites that were not directly exposed to radiation. They were particularly focused on what the team called "cold" tumors – tumors that do not respond to immunotherapy, which are identified by biomarkers such as low mutation, and low production of a protein called PD-L1 or other markers of low response to immunotherapy.

What the team found was that after radiation these "cold" tumors, far from the site of radiation, experienced substantial remodeling of the tumor microenvironment. The result was that these remote sites "warmed" up and became inflamed exhibiting results of strong immune activity including the expansion of new and pre-existing T cells that attack cancer. 

Taking samples of these newly "inflamed" tissues in the lab, the researchers confirmed that the T cells were expanding in patients who had received the radiation and immunotherapy.

When they tracked the patient outcomes from the clinical trial, the team observed that patients who received the radiation therapy and immunotherapy had better outcomes than the patients who had immunotherapy alone. Patients in the radiation arm had median progression free survival (PFS) of 5.2 months compared to a median of 1.81 months in the immunotherapy alone group.

The researchers concluded that the clinical results suggest that radiation therapy might help overcome immunotherapy resistance in certain lung cancer patients. 

Sources: Johns Hopkins Medicine press release and Nature Medicine