Radiation‐induced heart disease (RIHD) is a serious complication of thoracic radiotherapy, and its pathogenesis involves systemic immune alterations. To elucidate these mechanisms, we profiled peripheral blood mononuclear cells (PBMCs) from patients before and after thoracic radiotherapy using single‐cell RNA sequencing (scRNA‐seq), with key findings validated via multiparameter flow cytometry and ELISA assays. Our analysis revealed that radiotherapy markedly reshaped the immune composition, expanding innate myeloid cells (monocytes and neutrophils) and reducing lymphocytes (T and NK cells); these compositional shifts were independently confirmed by flow cytometric analysis. Cell–cell communication networks showed that postradiotherapy monocytes evolved into central signaling hubs, exhibiting heightened proinflammatory ligand–receptor interactions. Consistent with this, monocytes showed broad transcriptional reprogramming with upregulation of canonical inflammatory pathways (IL‐6/STAT3, TNF/NF‐κB) and metabolic regulators (mTORC1, glycolysis). ELISA assays corroborated these transcriptomic signatures, demonstrating significantly elevated plasma levels of IL‐6 and TNF‐α post‐treatment. Notably, scRNA‐seq identified a selective expansion of the highly plastic intermediate (CD14++CD16+) monocyte subset, a specific population shift further verified by flow cytometry. These intermediate monocytes exhibited an immature, progenitor‐like profile and were enriched at the origin of a Monocle3 pseudotime trajectory. Trajectory analysis indicated they differentiate into mature classical monocytes that upregulate proinflammatory effector genes such as S100A8, S100A9, and S100A12. Furthermore, pseudotime gene clustering revealed a functional bifurcation in monocyte behavior: one module drove inflammatory activation, while a second module simultaneously engaged oxidative stress responses and antioxidant defenses (e.g., glutathione metabolism). In summary, by integrating single‐cell transcriptomics with experimental validation, we demonstrate that radiotherapy drives a systemic immune shift characterized by intermediate monocyte expansion and bifurcated programs of inflammation and stress adaptation. Intermediate monocytes emerge as key drivers of postradiotherapy inflammation, offering a potential cellular biomarker of RIHD risk and a target for immunomodulatory interventions to mitigate cardiovascular injury in cancer survivors.
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