Metabolism and Immunity-Adapted Radiotherapy (M.I.A.R): A Conceptual Framework for Overcoming the Therapeutic Plateau in Clinical Radiotherapy.

Despite technological advances in radiation therapy (RT), improvements in locoregional control of locally advanced disease remain limited, indicating a plateau in RT effectiveness. It is becoming increasingly clear that RT occurs within a dynamic metabolic microenvironment that merges oncogenic activity with metabolic and immune interactions. This includes responses to oxidative stress, regulation of cell death and survival signals, energy metabolism, protein synthesis, autophagy of molecules and organelles, and ultimately, the anti-tumor immune response. Each tumor, regardless of its histology, maintains a unique molecular and microenvironmental identity that influences its response to RT. Furthermore, RT acts as a cellular stressor that activates responses in cancer and stromal cells, impacting clinical outcomes. The concept of Metabolism and Immunity Adaptive Radiotherapy (M.I.A.R) recognizes that RT success depends not only on radiation dose and distribution but mainly on key interventions that alter and influence the biological environment before, during, and after therapy. It highlights the importance of an initial diagnostic workup, which is achievable with current tools, to identify tumor-specific oncogenes, metabolic, and immune profiles. Within the context of M.I.A.R., effective RT requires tumor preconditioning combined with concurrent use of drugs, including metabolism-targeting agents, to increase tumor sensitivity to radiation. Post-RT metabolic and immune interventions are essential for complete tumor eradication. This involves combining existing oncogene-targeting therapies with available immune treatments, supported by low-toxicity modulating drugs/agents with demonstrated preclinical activity against specific molecular and microenvironmental features. Overall, while MIAR remains a theoretical approach, existing preclinical and recent clinical data, e.g., those exploiting tumor hypoxia and re-oxygenation status, or post-RT immunotherapy, strongly support further dedicated investigation.