Radiotherapy has been shown to potentially induce systemic anti-tumor immunity, a phenomenon that may be further enhanced by immune checkpoint inhibitor (ICI) therapy. However, whether this phenomenon occurs following Gamma Knife radiosurgery (GKRS) for brain metastases (BMs) and its potential clinical implications remain poorly understood. We retrospectively analyzed 36 non-small-cell lung cancer (NSCLC) patients with multiple BMs treated with multi-session GKRS. Spontaneous tumor regression (STR) was defined as ≥ 30% volume reduction in non-irradiated tumors. Competing risks analysis and Cox regression were used to evaluate local progression, distant brain failure (DBF), and survival outcomes. In this study, 44% (16/36) of patients received ICI therapy. STR was observed in 38.9% (14/36) of the cohort. Comparative analysis revealed that patients received ICI therapy did not exhibited an improved overall survival (OS) (p = 0.46), but demonstrated a trend toward a higher incidence of STR compared to those without ICI therapy (56.3% vs. 25.0%, p = 0.056). Multivariable regression analysis identified the absence of STR as an independent risk factor for mortality (Hazard Ratio [HR], 7.69; 95% CI: 1.61-33.33; p = 0.009) and local tumor progression (HR, 5.05; 95% CI: 1.71-14.93; p = 0.003). A systemic anti-tumor immunity could be induced by GKRS and cause STR of non-irradiated tumors. Patients exhibiting this phenomenon demonstrate significantly improved survival rates and local tumor control compared to those without this response. These findings underscore the potential immunomodulatory role of GKRS and its clinical implications in the management of BMs.© 2025. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.