ESTRO 2025 - Abstract Book

S146

Invited Speaker

ESTRO 2025

associated antigens and the release of endogenous adjuvants from dying tumor cells. However, radiation-mediated abscopal effects in clinical settings are rare. Numerous clinical studies conducted to explore the efficacy of radio immunotherapy combination treatments have failed to demonstrate additive effects, highlighting the need to understand and address obstacles to effective in situ tumor vaccination. Intrinsic barriers within the tumor microenvironment (TME) often hinder efficient immune rejection. Factors such as disorganized vasculature, high interstitial fluid pressure, and mechano-biological signals impede T-cell migration into tumors. Additionally, resident and recruited cells in the TME can impair cytotoxic T-cell functions. In this lecture, different TME-mediated mechanisms of immunosuppression will be presented and the potential of radiotherapy to reprogram immune inhibitory mechanisms existing in the TME will be discussed. Furthermore, special emphasis will be given to the divergent biological effects elicited by different radiation regimens, or to the timing for when key biological processes are occurring after RT. Solid tumors typically exhibit increased tissue stiffness due to augmented deposition of extracellular matrix proteins, which hinders the access and motility of antitumor T-cells and therapeutic agents. Some RT regimens can transiently reduce intratumoral interstitial pressure and increase vascular permeability, however prolonged exposure to RT, such as in protracted regimens, can in turn induce matrix deposition and increased stiffness. The tumor vasculature, characterized by tortuous and leaky vessels, poses a significant obstacle to therapeutic access and immune cell infiltration. RT-mediated vascular normalization can enhance both drug delivery and antitumor immunity. On one hand, high doses of RT can cause extensive endothelial damage, reducing vascular flow and exacerbating hypoxia-driven immunosuppression. On the other hand, hypofractionated regimens with low RT doses could help to normalize tumor vasculature. Cancer-associated fibroblasts (CAFs) are important constituents of the TME and generally considered to promote an immunosuppressive TME. CAFs are capable of exerting both direct and indirect effects on tumor immunity through secretion of a plethora of cytokines, chemokines, proteases, and proangiogenic factors, as well as through the expression of immunoregulatory cell membrane receptors. The effects of RT on CAFs are poorly studied, however recent studies indicate that most of the described immunosuppressive effects are maintained in CAFs after irradiation. Myeloid-derived cells are important constituents of the TME, both numerically and functionally, and play central roles in regulating tumor vasculature and antitumor immune responses. Myeloid cells in tumors may exist in various differentiation stages and possess a susceptible immunomodulatory phenotype that can be influenced by radiation. Radiation-mediated changes on myeloid cells include killing of tumor-associated pools, recruitment of circulating progenitors, repolarization, and reorganization. Bone marrow-derived cell recruitment following RT involves chemokine/receptors pairs such as SDF-1/CXCR4–7, CCL2/CCR2–4, and colony-stimulating factor-1 (CSF 1)/CSF-1R. Observed RT effects on inflammatory cells seem to depend on radiation regimens and the timing post RT. Overall, the effects of RT on the TME are highly dependent on tumor type, stage, and treatment protocol. Preclinical data has demonstrated that some specific RT-regimens may aid to counteract some of the described physical and biological barriers for efficient tumor immune attack. Additionally, intense efforts are taking place to explore the potential additive effects of drugs that target diverse elements of the TME. In this lecture, special focus will be given to novel strategies targeting CAFs and suppressive signals derived from them.