Fig. 2: Potential role of RT (fractionated low dose versus single high dose) on the tumor vasculature, tumor cell, and microenvironment.

A Main effects of RT on the immune response. High-dose RT triggers TREX1 resulting in clearance of cytosolic dsDNA. Multiple chemokines, cytokines, and growth factors secreted, upon RT, via cytosolic dsDNA/cGAS/STING signaling, promote the recruitment of immune cells. RT facilitates an immune response by inducing immunogenic cancer cell death and DAMPs, which activate antigen-presenting cells such as DCs PRRs, and prime CTLs, ultimately causing the release of cytokines, which not only exerts an immunosuppressive role by potentiating PD-L1 level on tumor cells but also drives immune cell recruitment by upregulating leukocyte adhesion molecules in the vessel wall. B Main effects of RT on the vasculature. Single high-dose RT triggers apoptosis and senescence of endothelial cells by upregulating ALK5 and sphingomyelinase, leading to vascular regression and collapse and eventual vasculogenesis and angiogenesis. Fractionated low-dose irradiation upregulates angiostimulatory growth factors, inducing vascular growth and tissue perfusion by potentiating diverse endothelial cell functions, such as migration, proliferation, and sprouting tube formation.