Thymic epithelial tumors at the crossroads of immunity, autoimmunity, and immunotherapy.

Thymic epithelial tumors (TETs) sit at a unique intersection of cancer, central tolerance, and autoimmunity. These tumors arise in the thymus, an immune-rich organ responsible for T-cell education, and despite their low tumor mutational burden (TMB) and microsatellite stability, they display paradoxical behavior under immune checkpoint inhibition. This review synthesizes data on thymic biology, paraneoplastic autoimmunity, molecular profiling, and clinical trials of immune checkpoint inhibitors (ICIs) in thymoma and thymic carcinoma. We describe how disruption of autoimmune regulator (AIRE)/Fez family zinc finger 2 (FEZF2)-driven tissue-restricted antigen expression and impaired regulatory T-cell generation collectively permit the escape of autoreactive T cells and foster classic paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, and Good syndrome. We then link these baseline defects to the high frequency and severity of immune-related adverse events observed in TET patients treated with ICIs, despite only modest response rates. Emerging "harm axis" biomarkers, including autoantibody profiles and composite T- and B-cell perturbations, may help stratify risk and guide treatment selection. Finally, we review rational therapeutic strategies such as vascular endothelial growth factor-tyrosine kinase inhibitors-ICI combinations, radiotherapy-ICI approaches, perioperative immunotherapy, and emphasize the need for biomarker-enriched trial design. TETs provide a powerful model to understand how failure of central tolerance can simultaneously sensitize tumors to immune attack and prime patients for catastrophic toxicity, with implications that extend to other low-TMB, immune-infiltrated malignancies.