Radiation therapy enhances immune environment in brain metastases, improving treatment response

by University of Texas MD Anderson Cancer Center

edited by Sadie Harley, reviewed by Andrew Zinin

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A new study led by researchers at The University of Texas MD Anderson Cancer Center demonstrated that preoperative radiation therapy for brain metastases not only targets tumor cells directly but also can activate immune pathways that can make tumors more receptive to immunotherapy.

The study, published in Clinical Cancer Research, showed that radiation therapy is effective both in eliminating cells directly and in reshaping the surrounding immune landscape by recruiting and activating T cells, suggesting that radiation-immunotherapy combination strategies could improve patient outcomes.

The results also highlighted T cell receptor diversity in the tumor microenvironment as a potential prognostic biomarker for predicting treatment response.

The research was co-led by Jason Huse, M.D., Ph.D., professor of Anatomic Pathology; Nuhad Ibrahim, M.D., professor of Breast Medical Oncology; and Alexandre Reuben, Ph.D., assistant professor of Thoracic/Head & Neck Medical Oncology.

"Brain metastases are highly complex, and effective treatment requires addressing both the tumor and its microenvironment in order to engage the immune system," Huse said.

"By enhancing T cell diversity and antigen presentation within tumors, radiation ultimately transforms the immunosuppressed tumor microenvironment into a more responsive one, providing a strong biological rationale for radiation-immunotherapy combination strategies to improve patient outcomes."

Why are brain metastases so hard to treat?

Brain metastases, which are tumors that spread to the brain from cancers elsewhere in the body, remain a major clinical challenge, with limited treatment options and poor survival outcomes. While many cancers respond to immunotherapy, the brain tumor microenvironment is immunologically "cold," meaning it suppresses immune responses against the tumor. Additionally, the blood-brain barrier prevents many treatments from reaching tumors in the brain.

Radiation has emerged as a potential treatment option for brain tumors, including brain metastases, and is associated with antitumor immune responses. However, it is not yet clear which specific immune pathways and components are activated by this approach.

To investigate, the researchers conducted an integrated profiling analysis using RNA and T cell receptor sequencing in tissue samples from 306 patients with brain metastases that arose from either breast or lung cancer. Additionally, the researchers studied patient samples from an ongoing clinical trial led by Debra Nana Yeboa, M.D., associate professor of Central Nervous System Radiation Oncology, which compared preoperative and postoperative radiation therapy, to further characterize the immune microenvironments.

What made radiation therapy effective in the tumor microenvironment?

Radiation therapy is effective because it not only directly damages tumor DNA, but also causes tumor cells to react in a way that releases antigens, or "danger signals." These signals enhance the recruitment and activation of cytotoxic T cells into tumors, resulting in a stronger, targeted response.

In doing so, radiation therapy increases inflammatory cytokines and upregulates immune checkpoints that make tumors more visible and responsive to immunotherapy. Additionally, radiation alters blood vessels within tumors to facilitate immune cell entry and reduces or reprograms suppressive myeloid cells.

"Rather than the traditional approach focused on overcoming the blood-brain barrier for systemic therapy, these results show that it may be more beneficial to shift the focus to the microenvironment of the metastatic brain lesion," Ibrahim said.

"Not only does it improve the outcomes of immunotherapy, but it potentially extends those benefits to other areas that are not directly involved in radiation, which is a step in the right direction."

What do these results mean for patients?

While these results are retrospective and observational, the research team is now validating these findings in larger, prospective clinical trials to explore the potential of combining radiation and immunotherapy as therapeutic strategies in patients with brain metastases.

Overall, these results suggest that T cell diversity could be a useful way to determine which patients are more likely to respond to the combination of radiation and immunotherapy.

Publication details

Kazutaka Fukumura et al, Ionizing Radiation Enhances Prognostically Significant Cellular Immunity Programs in the Brain Metastasis Microenvironment, Clinical Cancer Research (2026). DOI: 10.1158/1078-0432.ccr-25-3525

Journal information: Clinical Cancer Research

Key medical concepts

Brain MetastaseRadiation TherapyImmunotherapy

Clinical categories

OncologyNeurology Provided by University of Texas MD Anderson Cancer Center Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

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