Radiotherapy is a central part of the treatment for many cancer types. Locally advanced carcinomas are treated with multimodal combinations with surgery, chemotherapy, and/or molecularly tailored drugs. Recent discoveries have stimulated new clinical trials evaluating the benefits of targeting the DNA damage response, DNA repair, or tumor immune escape with the goal of enhancing the efficacy of radiotherapy. Yet only a fraction of patients responds to such tailored treatments; others do initially not respond, or develop resistance, metastasis, or adverse effects. The inter-patient and inter-tumor heterogeneity in efficacy and toxicity of therapies involving radiotherapy offers largely unexploited avenues for a successful individualization of radiotherapy. So far, radiobiological research aimed at the integration of precision oncology strategies into clinical radiotherapy is still underrepresented. To fill this gap, the proposed RTG will create a multidisciplinary team of highly qualified basic and clinical scientists to explore how the heterogeneity, plasticity, and dynamics of the radiation responses of cancer cells, stromal, and immune cells in tumor and normal tissues affect therapy outcomes. The scientific goal is to discover biological principles underlying individual differences in radiosensitivity, adaptive resistance, and toxicity by translating results from studies using preclinical models and patient samples into interpretable computational models. Thereby we will discover actionable vulnerabilities and valid stratification markers suited to discriminating responders from non-responders and detecting patients at high risk of failure or adverse effects.