Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy

Abstract

Radiation 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.

Keywords: artificial intelligence; brain metastases; cGAS-STING; circulating biomarkers; immunotherapy; necrosis; stereotactic radiosurgery.

Figure 1

cGAS-STING Pathway: Radiation-induced DNA damage leads to accumulation of double-stranded DNA (dsDNA) in the cytosol of tumor, stromal, endothelial, and immune cells via (1) generation of micronuclei, (2) leakage of mitochondrial DNA (mtDNA), and (3) uptake of extracellular dsDNA from neighboring apoptotic cells via exosomes. Cytosolic cGAS undergoes reconfiguration and dimerization to form an activated state when bound to dsDNA. This allows the conversion of ATP and GTP to 2′,3′-cGAMP, which acts as a messenger molecule. Both cGAMP and dsDNA can act as paracrine signaling factors to activate cGAS-STING in neighboring cells, including dendritic cells (DCs). In the presence of cGAMP, STING located on the endoplasmic reticulum oligomerizes with TBK1 and undergoes phosphorylation. This then allows phosphorylation and activation of IRF3, which translocates to the nucleus to induce type 1 IFN signaling, which then targets DCs and other myeloid cells. By this mechanism, cGAS-STING mediates DC maturation, migration, and costimulatory molecule expression, including the expression of MHC 1 receptors. This leads to the priming of CD8+ cytotoxic T-cells, which then induce target cell death via granzymes, perforins, and activation of death receptor signaling. Thus, cGAS-STING serves as a crucial bridge between radiation-induced DNA damage and both innate and adaptive anti-tumor immune responses. Figure created with BioRender.com.

Figure 2

Radiation necrosis pathophysiology. (A) The tumor microenvironment of a brain metastasis prior to radiation includes a conglomerate of tumor cells surrounded by resident microglia, astrocytes, and neurons. Circulating immune cells and red blood cells are separated from the brain parenchyma by an intact blood-brain barrier made up of endothelial cells and pericytes. (B) The tumor microenvironment following radiation therapy is characterized by the upregulation of pro-inflammatory and innate immune responses. In the setting of necrotic tumor cells, reactive oxygen species (ROS), type 1 IFNs, TNFα, and interleukins are upregulated. Gliosis, with reactive astrocytes and microglia, is seen. Damage to pericytes, endothelial cells, and other resident cell populations leads to hypoxia-induced VEGF and EGFR expression. A leaky blood-brain barrier allows for migrations of macrophages, dendritic cells, and cytotoxic CD8+ T-cells into the tumor microenvironment. Hemorrhage and thrombosis are additional hallmarks of necrosis. Figure created with BioRender.com.

Figure 3

Representative case of radiation necrosis following concurrent CTLA4/PD1 inhibition with SRS. (A) MRI confirms new left occipital melanoma metastasis (blue arrow). (B) The SRS treatment plan delivered several days later, after the receipt of ipilimumab/nivolumab. A and P (in red), denote anterior and posterior, respectively. (C) MRI demonstrating localization of biopsy-confirmed necrosis at the site of the previous left occipital metastasis (blue arrow) 16 months after SRS treatment. Radiation necrosis occurred within the high dose treatment volume.