Background
The thymus is essential for T-cell development during foetal life and childhood, but its importance in adults has long been debated because the organ progressively involutes with age. Traditional immunology often assumed that, after adolescence, peripheral T-cell expansion could largely compensate for declining thymic output.
Recently, three very important studies in 2023 and 2026 have fundamentally challenged this common assumption and highlighted the crucial importance of the thymus in adult life.
First study
Kameron A. Kooshesh, M.D., Brody H. Foy, D.Phil., David B. Sykes, M.D., Ph.D., Karin Gustafsson, Ph.D., and David T. Scadden, M.D. Health consequences of thymus removal in adults. New England Journal of Medicine 2023; 389:406-17. doi: 10.1056/NEJMoa2302892.
This clinical research investigated whether adult thymectomy is associated with adverse clinical outcomes.
Study Design
The study was a large retrospective observational analysis using the Mass General Brigham registry in Boston.
The investigators compared:
- adults who underwent thymectomy (1,420), with
- matched controls (6,021) who underwent similar cardiothoracic surgery without thymectomy.
Patients were matched for age, sex, race, preexisting infection, cancer, and autoimmune disease.
The authors performed immune profiling, cytokine analyses, T-cell receptor repertoire studies, and sjTREC measurements to evaluate new thymic T-cell production.
Main Findings
- Increased Mortality after Thymectomy
The most striking result was a substantial increase in long-term mortality: 8.1% in the thymectomy group versus 2.8% in controls 5 years after surgery and the survival worse was worse after 20 years. This effect remained significant even after excluding patients with thymoma, myasthenia gravis, preexisting cancer, infection or autoimmune disease.
- Increased Risk of Cancer
Patients who underwent thymectomy had approximately double the risk of developing cancer: cancer incidence was 7.4 % after thymectomy versus 3.7% in controls, and the long-term cancer risk also remained elevated.
- Cancers Were More Aggressive
Chart review showed that cancers in thymectomized patients were more numerous, more diverse, more aggressive (in particular, breast cancer), more metastatic, and more recurrent (17.1% after thymectomy versus 4.6% in controls. Cancer mortality was also increased (2.3% vs 1.0%).
The authors interpret these findings as evidence of impaired immune surveillance after loss of thymic function.
- Increased Autoimmune Disease
The association with autoimmunity was more nuanced.
In the full cohort, no major increase was initially seen. However, after excluding patients with preexisting disease, autoimmune disease became significantly more frequent after thymectomy (12.3% vs 7.9%, relative risk = 1.5).
Patients who underwent thymectomy also developed more autoimmune diagnoses per patient.
This suggests that, in adults, thymectomy modestly disrupts immune tolerance mechanisms.
- Persistent Reduction in New T-Cell Production
One of the most important mechanistic findings involved thymopoiesis. Even many years after surgery, thymectomized patients had markedly lower sjTREC counts in both CD4+ and CD8+ T cells.
This observation demonstrates that the adult thymus continues to generate new T cells for decades.
- Reduced TCR Diversity
T-cell receptor sequencing showed increased clonality, and reduced diversity of the TCR repertoire especially in patients who later developed cancer.
This is highly important conceptually because reduced TCR diversity limits immune adaptability, weakens tumour immune surveillance, and may promote immunosenescence.
- Proinflammatory Immune Signature
Cytokine analyses revealed chronic immune dysregulation after thymectomy with elevated proinflammatory cytokines, Th2 and Th17-associated signals, acute-phase inflammatory makers, but reduction of anti-inflammatory mediators such as IL-10 and IL-1Ra.
The authors interpret this as chronic low-grade inflammation resembling inflammaging and immune dysregulation.
Final Conclusion
This article represents one of the most important conceptual advances in modern thymus biology since the recognition of the thymus as the organ of central T-cell biology by Jacques F. A. P. Miller.
This pilot and pioneering study concludes that thymectomy in adults is associated with increased mortality, increased cancer risk, altered immune regulation, and persistent impairment of T-cell production.
The findings also demonstrate that the adult thymus remains biologically and clinically important, and that preservation of thymic tissue should be cautiously considered whenever surgically feasible.
Second Study
Simon Bernatz, Vasco Prudente, Suraj Pai, Asbjørn K. Attermann, Yumeng Cao, Jiachen Chen, Asya Lyass, Borek Foldyna, Leonard Nürnberg, Keno Bressem, Christopher Abbosh, Charles Swanton, Mariam Jamal-Hanjani, Michael T. Lu, Joanne M. Murabito, Kathryn L. Lunetta, Nicolai J. Birkbak & Hugo J. W. L. Aerts. Thymic health consequences in adults. Nature. 2026 Apr;652(8111):986-994. doi: 10.1038/s41586-026-10242-y
- Central Thesis of the Paper
The authors propose a major paradigm shift: the adult thymus remains biologically and clinically important throughout life, and preservation of “thymic health” is associated with longer survival, lower cancer incidence, lower cardiovascular mortality, reduced inflammation, and better metabolic health.
Traditionally, thymic involution was considered a normal and mostly inconsequential aspect of aging. This study argues the opposite: thymic decline is highly variable between individuals, preserved thymic function predicts healthier aging, accelerated thymic involution may actively contribute to disease susceptibility.
- Scientific Context
Especially influential was the 2023 study by David T. Scadden and colleagues showing increased mortality and cancer risk after thymectomy in adults. The present paper extends this idea from surgical thymectomy to the general population.
- Study Design
Cohorts: National Lung Screening Trial (NLST): 25,031 participants, longitudinal follow-up over 12 years, mortality and lung cancer outcomes; Framingham Heart Study (FHS): 2,581 participants, cardiovascular outcomes, metabolic and inflammatory profiling; Total: 27,612 individuals.
This scale is unprecedented in thymus research.
- Major Technological Innovation
AI-Based Quantification of “Thymic Health” (Figure 1)
The authors developed a deep-learning system analysing thoracic CT scans that:
- localizes the thymic region,
- extracts radiographic features,
- generates a continuous thymic health score from 0–100.
The AI model appears capable of identifying subtle structural signatures that are invisible with conventional radiology.
Figure 1. Illustration of thymic health as evaluated by an imaging-based proxy of thymic functionality, and two representative examples of individuals with high or average thymic health. The thymus bed is outlined in orange (adapted from Fig. 1 in the study by Bernatz S et al., Nature, 2026 Apr;652(8111):986-994. doi: 10.1038/s41586-026-10243-x).
- Main Findings
A. Thymic Health Predicts Longevity
One of the strongest findings: individuals with high thymic health had dramatically lower mortality in NLST with a 50% reduction in mortality risk. This is crucial because thymic involution could otherwise simply reflect biological aging.
B. Cancer Protection
High thymic health was associated with a lower lung cancer incidence and a lower lung cancer mortality. This strongly supports the idea that thymic maintenance preserves immune surveillance against cancer.
The finding aligns with theories linking declining T-cell repertoire diversity, impaired neoantigen recognition, cancer emergence with aging. This aspect is particularly important for immune-oncology.
C. Cardiovascular Protection
High thymic health predicted markedly reduced cardiovascular mortality.
The work strongly supports growing evidence that adaptive immunity, chronic inflammation, and T-cell dysregulation are central drivers of cardiovascular disease.
D. Metabolic Associations
Better thymic health is correlated with higher HDL, lower triglycerides, lower glucose, lower blood pressure, and lower obesity rates. The study therefore integrates the thymus into systemic metabolic aging.
E. Inflammation (“Inflammaging”)
One of the strongest mechanistic sections since poor thymic health is associated with elevated inflammatory mediators. The authors also show that chronic elevation of CRP over years predicts lower thymic health. This connects thymic involution directly to inflammaging
- Biological Interpretation
The study strongly argues that residual adult thymopoiesis matters and continuous T-cell renewal contributes to long-term health. This contradicts the old idea that peripheral expansion alone is sufficient at advanced age.
- Clinical Implications
A. Biomarker of Biological Aging
Thymic health may become a biomarker of immune age, a predictor of resilience, and a marker of healthy longevity.
B. Preventive Medicine
The paper suggests thymic decline may be modifiable through some possible interventions: exercise, weight reduction, smoking cessation, anti-inflammatory therapies, metabolic optimization, and sleep improvement.
C. Thymic Regeneration
The article explicitly mentions regenerative approaches that intersect with IL-7 biology, FOXN1, thymic epithelial regeneration, stem-cell approaches, endocrine modulation, and thymic rejuvenation programs. This field may now accelerate substantially.
- Strengths of the Study
Very few thymus studies reach this level of statistical power.
- Limitations
AI Interpretability
The “thymic health” metric remains partly abstract. Although biologically plausible, it is neither identical to direct thymopoietic output, nor directly validated against sjTREC quantification or thymic biopsies.
Imaging Standardization
Different scanners and acquisition protocols may influence the AI model and the authors acknowledge this limitation clearly.
Third Study
Simon Bernatz, Vasco Prudente, Suraj Pai, Asbjørn K. Attermann, Alessandro Di Federico, Andrew Rowan, Selvaraju Veeriah, Lars Dyrskjøt, Leonard Nürnberg, Joao V. Alessi, Patrick A. Ott, Elad Sharon, Allan Hackshaw, Nicholas McGranahan Christopher Abbosh10, Raymond H. Mak1,2, Danielle Bitterman, Mark Awad, Biagio Ricciuti, Charles Swanton, Mariam Jamal-Hanjani, Nicolai J. Birkbak & Hugo J. W. L. Aerts. Thymic health and immunotherapy outcomes in patients with cancer. Nature 2026;652:995-1003. doi: 10.1038/s41586-026-10243x.
General overview
This important study published by the same group in the same issue of Nature investigates whether the functional state of the adult thymus influences the efficacy of cancer immunotherapy. Using the concept of thymic health outlined above, as well as quantified through deep-learning analysis of routine thoracic CT scans, they show that better thymic health is associated with improved outcomes in patients treated with immune checkpoint inhibitors (ICIs).
This work also challenges the long-standing dogma that the adult thymus is largely irrelevant after adolescence and instead supports the idea that thymic activity persists throughout adult life and remains clinically meaningful.
Central hypothesis
The authors hypothesize that the efficacy of cancer immunotherapy depends not only on tumour-related factors (such as PD-L1 or tumour mutational burden) but also on the host’s immune competence, particularly thymic function.
This is a major conceptual shift in immuno-oncology, where biomarkers have traditionally been tumour-centric.
Summary of the Study
Although immunotherapy has revolutionized cancer treatment, many patients still experience limited benefit, highlighting the urgent need for improved biomarkers. Although immunotherapy is founded on unleashing T cells, most existing biomarkers remain tumour-centric and mainly overlook host immune competence.
The thymus is a key immune organ that is crucial for T cell maturation, and the authors hypothesized that thymic functionality is associated with immunotherapy outcomes. Here they show that thymic health, a radiographic measure of thymic functionality, is strongly associated with immunotherapy outcomes across several cancer types. Using a deep-learning framework applied to routine computed tomography images, they quantified thymic health in a pan-cancer cohort of 3,476 patients receiving immune checkpoint inhibitors. In patients with non-small cell lung cancer, higher thymic health was associated with reduced risks of progression and all-cause mortality.
These associations remained significant across clinically relevant levels of programmed death ligand 1 (PD-L1) and tumour mutation burden. In the prospective TRACERx lung cancer study, thymic health was positively associated with T-cell receptor diversity and T-cell receptor excision circles, and correlated with immune-system signalling pathways, supporting radiographic thymic health as a proxy for thymic activity and adaptive immune competence. Analysis across patients with melanoma, breast cancer or renal cancer demonstrated pan-cancer relevance.
Together, these findings identify thymic health as a previously unrecognized, tumour-agnostic determinant of immunotherapy efficacy, with potential implications for patient stratification, treatment timing and the development of immune-rejuvenating strategies in precision immuno-oncology.
Author’s Affiliation
Vincent Geenen, MD, PhD – Emeritus Professor at University of Liège; Emeritus Research Director at FSR of Belgium, B-4000 Liège, Belgium; vgeenen@uliege.be
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