ESTRO 2025 Congress Report I Radiobiology track

Combining radiotherapy with immunotherapy is a promising approach, as radiotherapy can activate an anti-tumour immune response and act as an in situ vaccine. However, radiotherapy can also have immunosuppressive effects, making this approach less efficient. Much research is ongoing to understand the complex interaction between tumour cells and the tumour microenvironment (TME), and how this can be exploited or modified to increase radiotherapy outcome. This was reflected by many talks on the topic in both the radiobiology and clinical tracks at ESTRO 2025. I was especially thrilled by this symposium in the radiobiology track, titled “Therapy-shaping of the tumour microenvironment: How do the tumour-host immune cells' interactions affect radiotherapy outcome?” In this symposium, four leading experts in the field provided their data and reflections around this exciting topic.

The session was chaired by Zuzanna Nowicka from Poland and Michele Mondini from France.

The first speaker, Prof Fernanda Herrera from the University of Lausanne in Switzerland, presented her work on how low-dose radiotherapy (< 1 Gy) can reprogram the TME and convert immunologically cold tumours into hot, inflamed tumours in a talk entitled “Evaluating tumour microenvironment alterations pre- and post- radiation treatment”. In a mouse model for metastatic ovarian cancer, she demonstrated that such low doses induce immune infiltration and upregulation of molecules priming T-cells. This work led to the design of a novel radio-immunotherapy regimen (RACIM), integrating low-dose radiation with immune checkpoint inhibitors (anti-CTLA4, anti-PD1) to increase the priming and killing capacity of T-cells, immune-modulating agents (CD40 agonist) to increase the co-stimulatory capacity of antigen-presenting cells, and low-dose cyclophosphamide to deplete regulatory T-cells. This regimen was successful in mice, and promising results from a phase I study in patients with metastatic solid tumours were presented.

Dr Erik Wennerberg from the Institute of Cancer Research in Sutton, United Kingdom, continued with a talk entitled “Metabolic barriers to immunogenic radiotherapy response”. He discussed how the metabolic landscape of solid tumours can contribute to a hostile microenvironment for infiltrating immune cells. Cancer cells can convert essential metabolites, like ATP and NAD+, into immunosuppressive metabolites or use them as substrates to directly destroy infiltrating lymphocytes. A novel flow cytometry-based method to measure metabolic dependencies for multiple immune populations at the single-cell level was presented. This analysis, together with imaging-based assessments of mitochondrial dependencies, led to the identification of ART1, a mono-ADP-ribosyltransferase, as a central player in radiation-induced immune modulation. His work to elaborate this finding was presented, including preclinical studies showing that ART1-blockade in combination with hypofractionated radiotherapy delayed tumour growth and extended survival compared with radiotherapy or ART1 blockade alone.

The next speaker, Dr Leila Akkari from the Netherlands Cancer Institute, also focused on the metabolic cross-talk between cancer and immune cells. Her talk was titled “Dissecting and rewiring myeloid cell heterogeneity in cancer: Understanding therapy-induced changes”. She presented work on glioblastomas, which are highly refractory to treatment and show an inflammatory and immunosuppressive microenvironment. By using multi-omics analyses of preclinical brain cancer mouse models and patient material, her group has identified metabolically rewired tumour-associated macrophages (TAMs), myeloid cells, and regulatory T-cell subpopulations. Her studies further indicate that these subpopulations fuel cancer progression and resistance to standard of care and immunotherapy. Ongoing work investigating the underlying mechanisms for this cross-talk was presented. In particular, promising results suggesting a role of cholesterol-rich myelin debris in the glioblastoma microenvironment were discussed.

Inigo Martinez-Zubiaurre from The Arctic University of Norway ended the symposium with his talk entitled “Radiotherapy as a means to reprogram tumour microenvironment: Can it counteract immunosuppression?” In this lecture, different mechanisms of immunosuppression in the TME were presented, and the potential of radiotherapy to reprogram these mechanisms was discussed. He described important obstacles for immune cell infiltration, including increased tissue stiffness due to augmented deposition of extracellular matrix proteins and a leaky and tortuous tumour vasculature. Cellular populations with potential immune suppressive effects, like cancer-associated fibroblasts (CAFs) and myeloid-derived cells, were further discussed. A special emphasis was given on how the immunosuppressive effects are modulated by different radiation regimens, including hypofractionation and low-dose radiation. In addition, novel strategies targeting CAFs and suppressive signals derived from them were presented.

Heidi Lyng

Oslo University Hospital

Norway