Thyroid Immune-related Adverse Events Following Immune Checkpoint Inhibitors in NSCLC: Insights From Pharmacovigilance Data, a Retrospective Case-control Study, and Single-cell RNA Sequencing Dataset.

PURPOSE: Thyroid immune-related adverse events (irAEs) are common with immune checkpoint inhibitor (ICI) therapy in nonsmall cell lung cancer (NSCLC), but their drug-specific risks, clinical characteristics, and immune features remain incompletely understood. This study aimed to systematically characterize thyroid irAEs, identify relevant clinical factors, and explore preliminary immune features associated with thyroid irAEs.

METHODS

We integrated FDA Adverse Event Reporting System (FAERS) pharmacovigilance data, a single-center retrospective case-control analysis, and a publicly available peripheral blood single-cell RNA sequencing (scRNA-seq) dataset from ICI-treated NSCLC patients. Disproportionality analysis evaluated thyroid irAE signals across ICI classes and regimens. In the retrospective analysis, logistic regression assessed factors associated with thyroid irAE occurrence, initial clinical subtype, and progression from thyrotoxic phase to hypothyroidism. ScRNA-seq analysis explored preliminary immune features.

FINDINGS: Among 1022 FAERS thyroid irAE cases, anti-PD-1 monotherapy, particularly nivolumab, showed the strongest hypothyroidism signal, whereas nivolumab plus ipilimumab was most associated with hyperthyroidism. Rare but significant signals were also detected: thyrotoxic crisis with nivolumab plus ipilimumab (reporting odds ratio [ROR] = 20.11, n = 5) and pembrolizumab (ROR = 4.22, n = 4), Graves' disease with nivolumab plus ipilimumab (ROR = 9.05, n = 4), and exophthalmos with nivolumab (ROR = 11.87, n = 3). In the retrospective analysis, baseline TPOAb and/or TgAb positivity was the only factor associated with thyroid irAE occurrence (odds ratio = 10.55, 95% confidence interval: 4.57-28.89). Among patients with thyroid irAEs, TPOAb and/or TgAb positivity was associated with initial thyrotoxic phase presentation and earlier onset, whereas higher baseline TSH was associated with initial hypothyroidism presentation. Among patients with initial thyrotoxic phase, 58.9% progressed to hypothyroidism, with higher baseline TSH and BMI associated with progression. Exploratory scRNA-seq analysis suggested a shift from naive T cells toward cytotoxic effector CD8⁺ T cells, accompanied by activation of TCR signaling and ER-Golgi vesicle transport pathways.

IMPLICATIONS: This study identifies drug-specific thyroid irAE signals, clinically relevant risk factors and preliminary immune features associated with thyroid irAEs. Baseline thyroid autoantibody status, TSH level, and BMI support risk-adapted thyroid monitoring and clinical management, while the overall findings provide a basis for further validation in larger cohorts and mechanistic studies.