Abstract Background The thymus plays a crucial role in early life, serving as the primary source of T-cell development, a vital component of adaptive immunity. Despite its central role in immune biology, the thymus is not currently considered an organ-at-risk in Radiotherapy (RT). RT, a cornerstone of treatment for locally advanced non-small cell lung cancer (NSCLC), has effects extending beyond local tumor control. In particular, it can trigger immunogenic cell death, releasing tumor antigens that prime systemic antitumor immunity. These immune-mediated effects are particularly important when RT is combined with immunotherapy, where consolidation immunotherapy has been shown to improve survival after chemoradiation. Methods In this multicohort study, we assessed whether thymic irradiation was associated with distant metastases and all-cause mortality across 882 locally-advanced NSCLC patients treated with RT (RTOG-0617 n=460 | HARVARD-CRT n=422). For each patient, we measured the mean thymic radiation dose (MTD). Thymic health was determined based on thymic radiographic representation on CT scans, automatically inferred using a self-supervised deep learning model. Associations with clinical outcomes were assessed using multivariable Cox models, adjusting for key clinical factors. Sensitivity analyses evaluated the incremental contribution of MTD. To demonstrate the clinical feasibility of thymic sparing with modern RT techniques and AI-based volume delineation, we replanned the RT treatment plan in a representative case with high cumulative thymic dose exposure. Results In RTOG patients with preserved thymic health, higher thymic radiation dose was progressively associated with worse clinical outcomes. An MTD of 35Gy was identified as the lowest dose linked to a significant deterioration in outcomes. This threshold was validated in both cohorts, where exceeding the 35Gy MTD in patients with preserved thymic function was associated with increased risk of distant metastases (RTOG-0617: adjusted hazard-ratio aHR=1.32; p=0.002 | HARVARD-CRT: aHR=2.15; p=0.018) and worse overall survival (RTOG-0617: aHR=1.20; p=0.002 | HARVARD-CRT: aHR=2.02; p=0.014). No significant associations emerged in patients with low thymic health prior to radiation therapy. One-year follow-up imaging demonstrated dose-dependent declines in AI-quantified thymic health, supporting a mechanistic link between thymic irradiation and loss of immune competence. In a feasibility test case, thymic dose was successfully reduced below 35 Gy without compromising tumor coverage or cardiopulmonary constraints. Conclusions Thymic radiation exposure was independently associated with higher risks of metastasis and death in NSCLC patients with preserved thymic function. These findings suggest that the thymus should be recognized as an organ-at-risk in radiotherapy and that thymus-sparing strategies may be crucial to preserve immune health and improve patient outcomes. Citation Format: Vasco Prudente, Simon Bernatz, Suraj Pai, Katelyn M. Atkins, Keno Bressem, Christian V. Guthier, Leonard Nürnberg, Christopher E. Kehayias, Christopher Abbosh, Charles Swanton, Mariam Jamal-Hanjani, Nicolai Juul Birkbak, Raymond H. Mak, Hugo Aerts. Thymic radiation and oncologic outcomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2327.
Prudente et al. (Fri,) studied this question.