## 4 Radiation and the Impact of the Tumor Microenvironment  
Understanding the complex interplay between the tumor microenvironment (TME), tumor stroma ratio (TSR), tissue hypoxia, and the effects of radiation therapy on cancer biology is essential for developing effective treatment strategies. The TME and TSR play critical roles in tumor progression, metastasis, and response to therapies, including radiation and immunotherapy. TME is a complex milieu composed of a stroma of various cell types, extracellular matrix (ECM) components, and signaling molecules that can promote tumor growth, angiogenesis, and immune suppression [32]. The TSR reflects the proportion of stromal tissue to cancerous tissue within a tumor, with a lower TSR indicating a more abundant tumor stroma. A low TSR, defined as greater than 50% of stroma on hematoxylin and eosin stains of surgical specimens, has shown a significant correlation with worse survival and more advanced disease. A low TSR was also correlated with worse clinicopathologic features in a wide variety of solid tumors including endometrial cancer in a systematic review and meta-analysis, although this effect was not seen in early cervical cancer [33].  
Hypoxia, a common feature of the TME, contributes to tumor progression, therapy resistance, and immune modulation [34]. Hypoxia-driven angiogenesis results in abnormal, leaky blood vessels, further perpetuating a pro-tumorigenic microenvironment. Hypoxia can influence radiation response by reducing the effectiveness of ionizing radiation, as the latter relies on the presence of oxygen to create cytotoxic reactive oxygen species (ROS) that damage DNA [35; 36; 37]. In the case of SBRT, high doses of radiation can lead to more significant endothelial cell damage, potentially exacerbating hypoxia and limiting the efficacy of the treatment [38]. However, hypoxia-targeting strategies, such as combining radiation therapy with anti-angiogenic agents, can help overcome these challenges and enhance the therapeutic outcome [39].  
SBRT, with the delivery of higher doses of radiation per fraction compared to standard fractionation, can lead to more pronounced immune-stimulatory effects. Hypoffractionated regimens have been shown to modulate the tumor vasculature, potentially overcoming the negative effects of tissue hypoxia on radiation response. SBRT can induce a strong abscopal effect, wherein local radiation therapy results in the regression of distant, non-irradiated tumor sites through systemic immune activation [40; 41; 42; 43; 44].  
While SBRT has shown favorable local control in ROMGC, out-of-field progression remains a significant cause of decreased overall survival. Additionally, radiation-induced damage in SBRT has been shown to trigger the immune response via the release of tumor antigen and damage-associated molecular patterns (DAMPs), causing the abscopal effect [45; 46]. Although this phenomenon has been cited in the literature for decades, it has been only seen in case reports, pre-clinical and translational studies. The interactions between SBRT and checkpoint inhibitors have shown synergistic effects, resulting in improvements in overall survival and objective response rates as well as demonstrating safety in non-gynecologic advanced or metastatic cancers; however, data including gynecologic malignancies are limited [47; 48; 49].  
The interactions between the TME, TSR and tissue hypoxia significantly impacts the response to radiation. The synergistic effects of combining radiation therapy, such as SBRT, with immunotherapy, have shown promising results in enhancing treatment efficacy and modulating the immune system to target cancer cells.