The Continuum of Thyroid Disorders Related to Immune Checkpoint Inhibitors: Still Many Pending Queries

SIMPLE SUMMARY: To capitalize on the revolutionary anticancer efficacy of immune checkpoint inhibitors (ICPi) in an expanding list of tumors, including hematological malignancies, it is mandatory to mitigate the immune-related (ir) adverse events, among which prevail the ir thyroid disorders. Currently, most available data on ir thyroid disorders are derived from solid tumors. Our review provides a comprehensive and updated overview of ir thyroid disorders, dissecting several intriguing issues, namely: (i) the elusive biological background, (ii) the epidemiological profile, (iii) the clinical spectrum, (iv) the diagnostic and therapeutic algorithms, (v) the predictive value of antithyroid antibodies for the development of ir thyroid disorders, and (vi) the prognostic significance. To contribute to the decision-making, this review provides an on-hand presentation of the latest reviews, meta-analyses, and pharmacovigilance studies addressing ir thyroid disorders, as well as of the most widely applied treatment guidelines. The current challenges and future perspectives, as regards a tailored approach to ir thyroid disorders, are critically discussed. ABSTRACT: Background: Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors. Methods: The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1). Results: With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies. Conclusions: Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.