HOUSTON, SEPTEMBER 22, 2026 ― Researchers at The University of Texas MD Anderson Cancer Center have identified a previously unknown pathway that prostate tumors leverage to suppress the immune system by reshaping the tumor microenvironment to resist treatment. A combined targeted therapy approach improved antitumor responses and prolonged survival in preclinical models of castration-resistant prostate cancer .
The study, published in Cancer Discovery , was led by Di Zhao, Ph.D. , associate professor of Experimental Radiation Oncology , and Nicholas Navin, Ph.D. , chair of Systems Biology . The findings suggest that tumors use this pathway as a backup physical defense and may explain why therapies targeting the B7-H3 immune checkpoint may show limited efficacy when used alone.
“Our study shows that the immune checkpoint B7-H3 does more than put the brakes on the immune system; it also reshapes the cells surrounding a tumor to help cancer grow and resist treatment,” Zhao said. “By uncovering how this process works, we identified a promising strategy that combines B7-H3-targeted therapy with MEK inhibition. These findings could help guide more effective, personalized treatments for patients whose tumors are unlikely to respond to B7-H3 therapy alone.”
Why is advanced prostate cancer difficult to treat?
Advanced prostate cancer, particularly castration-resistant prostate cancer, often becomes resistant to standard hormone therapies and has shown limited response to many immunotherapies. Researchers believe the problem might involve the surrounding tumor microenvironment, which includes myeloid-derived suppressor cells (MDSCs) that can make it harder for the immune system to recognize and destroy tumors. Cancer-associated fibroblasts also contribute to this microenvironment by creating a dense tissue barrier that can block immune cell infiltration and limit the ability of drugs to enter tumors.
What did the researchers discover about B7-H3 in this study?
B7-H3 is an immune checkpoint protein that is highly expressed in many cancers and already is being evaluated as a therapeutic target. Using genetically engineered preclinical models of castration-resistant prostate cancer, single-cell sequencing and immune profiling technologies, researchers found that B7-H3 directly interacts with a subset of immune cells known as monocytic MDSCs, triggering a signaling pathway that pushes cells into a senescent, or aged-like, state. These senescent cells release inflammatory molecules that change the surrounding environment and produce signals that attract additional suppressive immune cells.
Blocking B7-H3 reduced the number of suppressive MDSCs and slowed tumor progression, but MDSCs then produced higher levels of a protein that triggered fibroblasts to reinforce the tumor’s structural barrier.
Does targeting both B7-H3 and the signaling pathway at the same time overcome resistance?
Combining B7-H3-targeted therapy with trametinib, a Food and Drug Administration-approved MEK inhibitor that targets the same signaling pathway, successfully suppressed tumor growth and prolonged survival more effectively than either treatment alone. Further analysis showed that the combination reduced suppressive MDSCs, limited fibroblast-related tissue remodeling and increased T cell infiltration into tumors.
What does this mean for patients with advanced prostate cancer?
These results are preclinical and need further examination and validation before they can be translated into the clinic, but they provide strong evidence that this combination approach could help guide future clinical trial development for patients with advanced prostate cancers.
The researchers plan to continue studying this signaling pathway and its role in regulating interactions between immune and stromal cells to understand how these pathways function, given B7-H3’s abundance across different cancer types.
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This research was supported in part by the National Institutes of Health/National Cancer Institute, the Cancer Prevention and Research Institute of Texas (CPRIT), the Prostate Cancer Foundation, the U.S. Department of Defense, and UT MD Anderson institutional funding. A full list of collaborating authors and their disclosures can be found with the full paper in Cancer Discovery .
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Cancer Discovery