Cardio-immune crosstalk in novel radioimmunotherapy: implications for tumor immune remodeling, radiosensitization, and cardiac safety

Emerging radiotherapy modalities are reshaping cancer treatment by combining improved physical dose delivery with distinct immunobiological effects. FLASH radiotherapy, boron neutron capture therapy, spatially fractionated/lattice radiotherapy, proton and carbon-ion radiotherapy, and immunomodulatory stereotactic body radiotherapy can promote immunogenic cell death, innate immune sensing, antigen presentation, and effector lymphocyte responses, but may also induce checkpoint signaling, suppressive myeloid programs, regulatory T-cell activity, and other mechanisms of adaptive radioresistance. As these approaches are increasingly integrated with immunotherapy, their therapeutic window should be defined not only by tumor control but also by immune-mediated effects in normal tissues. This review focuses on cardio-immune crosstalk as an underexplored dimension of novel radioimmunotherapy, particularly in thoracic malignancies. We discuss how pathways that support tumor radiosensitization—including cGAS–STING–type I interferon signaling, myeloid–stromal remodeling, and checkpoint-regulated T-cell activation—may also perturb cardiac immune homeostasis after cardiac radiation exposure and systemic immune activation. We further examine how radiation modality, spatial dose distribution, dose rate, and cardiac substructure exposure may modify this balance. Direct characterization of cardiac immune responses remains limited for several emerging radiotherapy modalities, highlighting an important translational gap. Finally, we propose an integrated tumor–blood–heart framework combining tumor-response biomarkers, systemic immune profiling, and markers of cardiac vulnerability for future risk stratification and longitudinal assessment. This framework is conceptual and requires prospective clinical validation. Defining tissue-specific immune responses may help optimize novel radioimmunotherapy to maximize durable antitumor immunity while preserving cardiovascular safety.