Glycoprotein Nonmetastatic B⁺ Myeloid-Derived Suppressor Cells Mediate Radiation-Induced Immune Suppression in...

Stereotactic body radiation therapy (SBRT) provides excellent local control for localized prostate cancer (PC); however, systemic relapse remains the primary cause of death in high-risk patients, underscoring the need to understand and therapeutically address radiation-induced immune suppression. Here, we identify a previously unrecognized myeloid checkpoint pathway driven by glycoprotein nonmetastatic B (GPNMB⁺) myeloid-derived suppressor cells (MDSCs) as a dominant systemic response to clinical SBRT and demonstrate a tractable strategy to counter it.

We used paired peripheral blood samples from patients treated with SBRT to measure systemic MDSCs by flow cytometry, followed by ex vivo functional assays with patients' peripheral blood mononuclear cells. For further characterization, we used a syngeneic PC RM-9 tumor model. quantitative polymerase chain reaction and luciferase assays determined the mechanism observed.

We observed a selective and reproducible expansion of GPNMB⁺ MDSCs accompanied by enhanced T-cell suppression. GPNMB blockade in patients' peripheral blood mononuclear cells rapidly and consistently restored T-cell activity, directly supporting the clinical feasibility of targeting this pathway. Likewise, in tumor-bearing mice, radiation upregulated GPNMB on MDSCs and its ligand syndecan-4 on tumor-infiltrating T cells. Therapeutically, combining anti-GPNMB antibody with radiation significantly improved local tumor control and reduced metastatic burden compared with radiation alone and outperformed programmed death-ligand 1 blockade. Transcriptomic and mechanistic analyses identified melanocyte-inducing transcription factor as a key regulator of radiation-induced GPNMB expression.

Together, these findings define an actionable radiation therapy→ MDSC → GPNMB myeloid checkpoint that suppresses T-cell immunity in PC and demonstrate that targeting this pathway reverses radiation-induced immune suppression across human and murine systems. This work establishes a strong translational rationale for integrating MDSC-targeted therapy with SBRT to improve systemic control in localized high-risk PC.