By Morgan Nwanguma
Radiation therapy, once regarded mainly as a local cancer treatment, is now proving capable of awakening the immune system in unexpected ways. New research shows that combining radiation with immunotherapy can turn resistant, “cold” lung tumors into targets for immune attack. This effect, where immune cells are activated throughout the body rather than only at the radiation site, remains rare and not fully understood—but patients whose tumors experienced this shift had significantly better outcomes.
According to scientists at the Johns Hopkins Kimmel Cancer Center Bloomberg~Kimmel Institute for Cancer Immunotherapy and the Netherlands Cancer Institute, radiation therapy can essentially “prime” tumors that normally resist immunotherapy, making them susceptible to treatment and leading to improved results. Their findings, published July 22 in Nature Cancer and supported by the National Institutes of Health, provide a promising new strategy for tackling hard-to-treat cancers.
The study focused on non-small cell lung cancer, comparing patients who received immunotherapy alone with those who first received radiation followed by immunotherapy. Researchers observed that the combination triggered a systemic anti-tumor immune response and yielded stronger clinical benefits in patients with tumors that typically show resistance. Clinically, the results suggest that radiation therapy may help overcome immunotherapy resistance in select groups of patients.
“For a fraction of lung cancers where we aren’t expecting therapy responses, radiation may be particularly effective to help circumvent primary resistance to immunotherapy; this could potentially be applicable to acquired resistance, too,” says senior study author Valsamo “Elsa” Anagnostou, M.D., Ph.D., co-director of the Upper Aerodigestive Malignancies Program, director of the Thoracic Oncology Biorepository, leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins.
For years, researchers have worked to understand why some tumors develop resistance to immunotherapy—a treatment that harnesses the body’s immune system to fight cancer—and how to prevent it. One proposed strategy involves radiation therapy, which can sometimes trigger a rare phenomenon known as the abscopal effect. When radiation kills tumor cells at a primary site, the dying cells release molecular fragments into the surrounding environment. In certain cases, the immune system detects these fragments, learns to recognize the tumor’s molecular “fingerprint,” and mobilizes immune cells throughout the body to attack cancer cells at distant sites, even those untouched by radiation.
This effect suggests that radiation could help immunotherapy work more effectively, even against tumors far from the original treatment site. However, little has been understood about the underlying biology of the abscopal effect or how to predict which patients might benefit.
To investigate, Valsamo Anagnostou and colleagues studied patients with lung cancer, collecting samples at multiple time points and from different locations in the body—not just the primary tumor. In collaboration with Willemijn Theelen and Paul Baas at the Netherlands Cancer Institute, who were leading a phase II clinical trial testing radiation followed by the PD-1 inhibitor pembrolizumab, the team analyzed 293 blood and tumor samples from 72 patients. Participants either received immunotherapy alone or radiation plus immunotherapy.
Using multiomic techniques—including genomics, transcriptomics, and cell-based assays—the researchers tracked immune activity both systemically and within tumor sites that were not directly exposed to radiation. Their focus was on so-called immunologically cold tumors, which typically resist immunotherapy. These tumors are marked by features such as low mutation burden, absence of the PD-L1 protein, or mutations in the Wnt signaling pathway.
The findings were striking: after radiation combined with immunotherapy, distant cold tumors showed a dramatic transformation in their microenvironment. What were once inactive, “cold” sites began to “warm up,” displaying inflammation, immune cell infiltration, and expansion of both new and existing T cells.
“Our findings highlight how radiation can bolster the systemic anti-tumor immune response in lung cancers unlikely to respond to immunotherapy alone,” says lead study author Justin Huang, who led the multiomic analyses. “Our work underscores the value of international, interdisciplinary collaboration in translating cancer biology insights to clinical relevance.” Huang received the 2025 Paul Ehrlich Research Award, which honors breakthrough discoveries by young investigators and their faculty mentors at the Johns Hopkins University School of Medicine.
Working with Kellie Smith, Ph.D., an associate professor of oncology at the Johns Hopkins Kimmel Cancer Center and a Bloomberg~Kimmel Institute for Cancer Immunotherapy researcher, Valsamo Anagnostou’s team studied patients who achieved long-term survival with combined radiation and immunotherapy. The researchers conducted functional tests to determine how the patients’ T cells were responding. In cell culture experiments, they confirmed that the T cells expanding in these patients were specifically recognizing mutation-associated neoantigens from their tumors.
Tracking outcomes from the clinical trial, the team also found that patients with immunologically “cold” tumors that became “warmed up” after radiation therapy had better survival rates than those who received immunotherapy alone.
“It was super exciting, and truly made everything come full circle,” says 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.”
Building on the same patient cohorts, the research team has also been studying how the body responds to immunotherapy by measuring circulating tumor DNA (ctDNA) in blood samples. These findings were presented on April 28 at the annual meeting of the American Association for Cancer Research in Chicago.
Co-authors on the study include Zineb Belcaid, Mimi Najjar, Daphne van der Geest, Dipika Singh, Christopher Cherry, Archana Balan, James R. White, Jaime Wehr, Rachel Karchin, Noushin Niknafs, and Victor E. Velculescu. Michel M. van den Heuvel of Radboud University Medical Center also contributed.
The work was supported by the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy and the National Institutes of Health (grant #CA121113).
Disclosures: Anagnostou has received research funding to Johns Hopkins University from AstraZeneca, LabCorp/Personal Genome Diagnostics, Delfi Diagnostics, and Bristol Myers Squibb over the past five years. She serves as a compensated advisory board member for AstraZeneca and Neogenomics and has received honoraria from Foundation Medicine, Guardant Health, and LabCorp/Personal Genome Diagnostics. She is also listed as an inventor on six patent applications related to cancer genomic analyses, ctDNA monitoring of therapeutic response, and immunogenomic features of immunotherapy response, which have been licensed to external entities. In accordance with Johns Hopkins University’s conflict-of-interest policies, both the university and the inventors are entitled to associated fees and royalties under these licensing agreements.
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