Immune checkpoint blockade as an accelerator of adrenal aging: a testable model linking low-grade cortical inflammation to proteostasis failure, LDLR/SULT2A1 suppression, and reduced DHEA output

Immune checkpoint blockade (ICB) unleashes antitumor immunity but frequently provokes enduring endocrine toxicities. We hypothesize that ICB accelerates adrenal aging by establishing chronic low-level inflammation within the adrenal cortex, with targeting vulnerability of the zona reticularis. Integrating a recently published human multiorgan aging proteome atlas and primate adrenal aging study with survivorship data after ICB therapy, we propose a testable signaling cascade: ICB-amplified interferon gamma (IFNγ)/ tumor necrosis factor (TNF)/ interleukin-1 signaling activates nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 1 (STAT1), suppressing sterol regulatory element-binding protein 2 (SREBP2)-low-density lipoprotein receptor (LDLR)-mediated cholesterol uptake; concurrent mitochondrial/endoplasmic reticulum stress drives proteome-transcriptome decoupling, loss of cytochrome b5 type A (CYB5A), and impaired cytochrome P450 family 17 subfamily A member 1 (CYP17A1) 17,20-lyase activity; inflammatory transcriptional repression of sulfotransferase family 2A member 1 (SULT2A1) with proteostasis decay reduces dehydroepiandrosterone (DHEA) sulfation. The net result is a persistent fall in DHEA/DHEA sulfate (DHEAS) with comparatively preserved cortisol-mirroring natural adrenal aging. We advocate prospective measurement of DHEAS, DHEA, adrenocorticotropic hormone (ACTH), and cortisol at baseline, during therapy, end of therapy, and 6-24 months post-therapy; if early DHEAS decline is confirmed, targeted interventions including DHEA replacement or glucocorticoid receptor antagonism warrant evaluation. This framework reframes certain endocrine immune-related adverse events as "accelerated organ aging," with implications for risk stratification, toxicity prevention, and survivorship care.