Simple SummaryAs the incidence and survival of patients with brain metastases improve, the burden of treatment-related neurotoxicities will increase for patients and healthcare systems. Radiation necrosis, or injury and inflammation to normal brain tissue, is an increasingly common and deleterious adverse effect of radiation therapy that can contribute to patient morbidity and mortality. We aimed to characterize the biological mechanisms that drive necrosis and the risks associated with multimodal therapy, including immunotherapy. This review additionally provides management guidelines and an overview of novel opportunities for investigation. Awareness of the presentation, risk factors, biological mechanisms, and management options for necrosis are crucial for optimal patient-centered care and discovery.AbstractRadiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.