Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

Radiotherapy is cytotoxic to tumor cells and is therefore a critical component of therapy for many malignancies, including glioblastoma (GBM). We now appreciate the value of the immunomodulatory effects of radiation that may be important to overall therapeutic success in some patients with this primary brain tumor. Although potentially beneficial immune-stimulating properties of radiotherapy treatment have been the focus of recent study, this modality is actually at the same time associated with the depletion of lymphocytes, which are crucial to the defense against neoplastic development and progression. In this review, we describe the association of systemic lymphopenia with poor tumor outcome, present evidence that radiotherapy is an important contributing cause of lymphodepletion, describe the systemic immune context of tumor and brain injury that contributes to immunosuppression, describe other contributing factors to lymphopenia including concomitant medications and treatments, and speculate about the role of the normal physiologic response to brain injury in the immunosuppressive dynamics of GBM. Radiotherapy is one significant and potentially actionable iatrogenic suppressor of immune response that may be limiting the success of therapy in GBM and other tumor types. Altered strategies for radiotherapy more permissive of a vigorous antineoplastic immune response may improve outcome for malignancy.

Improvements in systemic therapy continue to increase survival for patients with brain metastases. Updated dosimetric models are required to optimize long-term safety of stereotactic radiosurgery (SRS) for this indication. Patients at a single institution receiving SRS from December 2011 to December 2014 were retrospectively reviewed. Patients with radiographic progression of at least one lesion, and with at least 6 months of follow-up from the start of SRS were included. Grade 3 necrosis was defined as requiring surgical intervention. This data were combined with two additional published datasets to construct logistic models describing necrosis risk as a function of dose and volume. From our institution, 294 brain metastases across 57 patients in 139 treatment plans met inclusion criteria. Primary histologies included non-small cell lung cancer (n = 19), melanoma (n = 13), breast carcinoma (n = 9), renal cell carcinoma (n = 7), and other (n = 9). Median follow-up from SRS of first cranial metastasis was 21.7 months (range: 6.3-56.6) and median overall survival was 25.6 months (range: 6.5-56.6). There were eight cases of Grade 1-2 and two cases of Grade 3 necrosis. As a useful clinical reference point, 20 cc of total brain receiving a single-fraction equivalent dose ≥14 Gy corresponded to 12.1% risk for Grade 1-3 (P < 0.003) and 3.4% risk for Grade 3 necrosis (P < 0.001). These results compare favorably with the QUANTEC brain tolerance estimates for radiosurgery, providing optimism for lower toxicity in the modern era. Additional studies are needed to determine dose tolerance parameters across a broad spectrum of patients.

Glioblastoma recurrence between initial resection and standard-of-care adjuvant chemoradiotherapy (CRT) is a negative prognostic factor in an already highly aggressive disease. Re-resection with GammaTileⓇ (GT Medical Technologies Inc., Tempe, AZ) placement affords expedited adjuvant radiation to mitigate the likelihood of such growth. Here, we report a glioblastoma patient who underwent re-resection and GammaTileⓇ (GT) placement within two months of the initial gross total resection due to regrowth that reached the size of the original presenting tumor. The patient subsequently received concurrent temozolomide and 60 Gy external beam to regions outside of the brachytherapy range, fulfilling the generally accepted Stupp regimen. The patient tolerated the treatment without complication. The dosimetrics and implications of the case presentation are reviewed.

PURPOSE: Post-operative stereotactic radiation (SRT) is the standard-of-care for resected brain metastases. Implantation of cesium-131 collagen tiles (tile-based radiation therapy, TBRT) initiates focal radiation immediately after resection, potentially offering therapeutic and logistical advantages. ROADS: a randomized, open-label, non-inferiority, phase 3 trial ( NCT04365374 ) compared the safety and efficacy of resection with TBRT (R+TBRT) to resection with SRT (R+SRT) for patients with a newly diagnosed brain metastasis indicated for surgical resection. PATIENTS AND METHODS: Across 32 United States centers, patients were pre-operatively randomized 1:1 to resection R+TBRT or R+SRT. Any non-resected brain metastases received SRT post-operatively. Co-primary outcomes were time-to-surgical bed recurrence (SBR) and surgical bed recurrence-free survival (SB-RFS). Outcomes were analyzed using Cox proportional hazards models with stratification factors as covariates. Multiplicity was controlled by hierarchical testing. Analyses used the pre-specified modified intent-to-treat (mITT) population (patients who underwent surgery, had pathologic confirmation of brain metastasis, and had follow-up information). RESULTS: From April 2021 through August 2025, 230 patients were randomized (115 per arm); 204 of whom (103 R+TBRT, 101 R+SRT) comprised the mITT population. Median follow-up was 12.9 months. Median time-to-SBR was not reached (R+TBRT) versus 17.4 months (R+SRT) (hazard ratio [HR]: 0.06; 95% confidence interval [CI]: 0.01–0.46; p=0.0070). SB-RFS was improved with R+TBRT, with a median of not reached versus 10.9 months (R+SRT) (HR: 0.48; 95% CI: 0.30–0.76; p=0.0021). Overall adverse events did not appear to differ: 83 patients (79.0%, 95% CI: 70.0–86.4) (R+TBRT) versus 67 patients (80.7%, 95% CI:70.6–88.6) (R+SRT). CONCLUSION: For patients with newly diagnosed brain metastases requiring resection, R+TBRT significantly improved SBR and SB-RFS, demonstrating both non-inferiority and superiority.