Primary adrenal insufficiency induced by immune checkpoint inhibitors (ICIs): a case series and systematic literature review

Immunotherapy-induced primary adrenal insufficiency (Ir-PAI) is a rare complication of immune checkpoint inhibitors (ICI). The clinical presentation is typically heterogeneous, with complex clinical pictures that may overlap with those of other endocrinopathies. Therefore, Ir-PAI may represent a life-threatening condition, with a possible subtle or acute onset, a high risk of electrolyte disorders, and hemodynamic instability. The management of Ir-PAI in cancer patients treated with ICIs requires a multidisciplinary management, involving at least oncologists and endocrinologists, to reach an early diagnosis, to safely manage patients, and to guarantee higher compliance and adherence to ICI treatment. In this study, we aimed to systematically examine cases of Ir-PAI reported in the literature and to describe our clinical experience. A total of 12 patients with Ir-PAI were collected from a systematic literature review, including cases reported from January 2011 to June 2025. Four patients were instead diagnosed at our Institution. Therefore, the evaluation of all 16 patients with Ir-PAIs identified 11 males (68.8%). Median age at PAI onset was 65 years (IQR: 18). The most common symptom at the occurrence of Ir-PAIs was asthenia/fatigue in 13 patients (81.3%). Ir-PAIs occurred more frequently in patients treated with anti-PD-1 mAbs (9 cases, 56.3%), and the most prevalent primary tumors associated with Ir-PAIs were renal cell carcinomas in four patients (25%). Other concomitant endocrine toxicities in patients with Ir-PAIs were thyroid dysfunctions in 8 patients (50%), and hypogonadism in 2 patients (12.5%).Our systematic review shows that Ir-PAI is a rare but clinically relevant toxicity of ICIs.