Abstract Background: Immune checkpoint inhibitors (ICIs) depend on effective T-cell priming and renewal, yet current biomarkers focus primarily on tumor-intrinsic features (PD-L1, TMB). Because the thymus maintains naïve T-cell output and repertoire diversity, we hypothesized that an individual's thymic health represents a host-intrinsic determinant of ICI benefit. Methods: We developed a self-supervised deep learning model to quantify thymic function, here termed thymic health, from routine CT scans. Thymic health was independently evaluated in 3,476 patients treated with ICI for tumors of various entities. Associations with PFS and OS were assessed using multivariable Cox models adjusting for key epidemiological and clinical factors. Sensitivity analyses evaluated the incremental contribution of thymic health. Biological validation was performed in treatment-naïve NSCLC patients from TRACERx (n=464) using T-cell receptor (TCR) sequencing and plasma proteomics. Results: In patients with NSCLC (n=1,218), high thymic health was associated with significantly reduced risk of progression (HR 0.65; 95% CI, 0.54-0.77) and death (HR 0.56; 95% CI, 0.46-0.68); preserved after full multivariate adjustments for sex, age, PD-L1, TMB, ECOG, histology, treatment line and stratification by treatment type (P0.001). Adding thymic health improved model fit beyond demographic, clinical, and tumor-intrinsic variables (likelihood ratio P0.001). Importantly, including thymic health did not attenuate PD-L1 or TMB effects, indicating complementary, non-redundant prognostic information. Across PD-L1 and TMB strata, higher thymic health was consistently associated with improved PFS and OS (P0.03). In TRACERx, thymic health was positively associated with T cell receptor excision circles, i.e., T cell output, and correlated with greater peripheral and intratumoral TCR diversity and with proteomic signatures of adaptive immune activation, biologically supporting its role as a radiographic proxy for immune competence. Pan-cancer analyses across 2,258 ICI-treated patients (melanoma, renal, breast, and others) showed consistent positive associations between thymic health and improved outcomes. Conclusions: Thymic health was consistently associated with improved immunotherapy outcomes across cancer types and added independent information beyond PD-L1, TMB, and standard clinical variables. These findings support thymic health as a possible non-invasive, host-intrinsic biomarker with potential to refine patient stratification and advance precision immuno-oncology. Clinical trial identification: ClinicalTrials.gov: TRACERx, NCT01888601 Citation Format: Simon Bernatz, Vasco Prudente, Suraj Pai, Asbjørn Kjær, Alessandro Di Federico, Andrew Rowan, Selvaraju Veeriah, Lars Dyrskjøt, Leonard Nürnberg, João Victor M. Alessi, Patrick Ott, Elad Sharon, Allan Hackshaw, Nicholas McGranahan, Christopher Abbosh, Raymond H. Mak, Danielle S. Bitterman, Mark M. Awad, Biagio Ricciuti, Charles Swanton, Mariam Jamal-Hanjani, Nicolai Juul Birkbak, Hugo JWL Aerts. Radiographic thymic health as host-intrinsic determinant of immunotherapy outcomes across cancer types 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 1185.
Bernatz et al. (Fri,) studied this question.