Immunotherapy-Related Hypophysitis: A Narrative Review

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized oncology, providing a groundbreaking therapeutic option for patients with various advanced-stage cancers. While these treatments can significantly extend survival, they also carry a substantial risk of immune-related adverse events, among which hypophysitis is particularly detrimental to endocrine function. This narrative review synthesizes current knowledge on the pathogenesis, clinical features, diagnosis, and management of ICI-induced hypophysitis (IH) based on an in-depth analysis of the recent literature and clinical trials. The diagnosis of IH presents unique challenges due to its overlap with systemic symptoms commonly associated with the underlying malignancy. These symptoms can include asthenia, anorexia, headache, vomiting, weight loss, hypotension, dizziness, decreased libido, and visual disturbances. Diagnostic evaluation typically combines clinical assessment, hormonal profiling, and findings from magnetic resonance imaging (MRI). Effective management of IH requires a personalized, multidisciplinary approach, focusing on hormone replacement therapy and vigilant monitoring. Long-term care depends on the severity of hypophysitis, and the specific hormonal axes involved. This review aims to enhance awareness of the critical aspects of recognizing and managing IH, underscoring the importance of early diagnosis and timely intervention to reduce its long-term effects on patient quality of life.

Keywords: hypophysitis; immune checkpoint inhibitors; immunotherapy.

Figure 1

T-cell activation and differentiation evoked by the binding of TCR to MCH II, by CD28 to CD80/86, and by the concurrent binding of polarizing cytokines to their respective receptors on the T-cell surface. Created in BioRender. La Sala, D. (2025) https://BioRender.com/l40l288. Abbreviations: MCH II: major histocompatibility complex type II; CD4: cluster of differentiation 4; TCR: T cell- receptor; CD80/86: cluster of differentiation 80/86; CD28: cluster of differentiation 28; APC: antigen presenting cell; IFNγ: interferon-γ; IL-12: interleukin 12; IL-2: interleukin 2; IL-4: interleukin 4; IL-6: interleukin 6; IL-23: interleukin 23; TGF-β: transforming growth factor-β; IL-10: interleukin 10; Th1: T helper 1; Th2: T helper 2; Th17: T helper 17; T reg: regulatory T cells; TNFα: Tumor necrosis factor α; IL-4: interleukin 4; IL-5: interleukin 5; IL-9: interleukin 9; IL-13: interleukin 13; IL-17: interleukin 17; IL-22: interleukin 22; IL-10: interleukin 10.

Figure 2

The mechanisms by which the TCR activation signal is increased or suppressed by costimulatory or coinhibitory signals. Created in BioRender. La Sala, D. (2025) https://BioRender.com/d25o366. Abbreviations: MHC: major histocompatibility complex; CD80: cluster of differentiation 80; CD86: cluster of differentiation 86; TCR-CD3 complex: T cell receptor- cluster of differentiation 3 complex; CD28: cluster off differentiation 28; CTLA-4: cytotoxic T-lymphocyte–associated antigen 4.

Figure 3

Awakening of the immune response against tumor cells by monoclonal antibodies against CTLA4, PD1, or PDL1. Created in BioRender. La Sala, D. (2025) https://BioRender.com/t81f332. Abbreviations: DC: dendritic cell; MHC: major histocompatibility complex; TCR: T cell receptor; CD28: cluster of Differentiation 28; CTLA-4: cytotoxic T-lymphocyte–associated antigen 4; PD-1: programmed cell death protein 1; PD-L1: programmed cell death ligand 1.

Figure 4

Representation of the mechanism of action of CTLA-4 blocking antibodies on pituitary cells. The immune complex between antibodies and antigens recruits complement C1q molecules that active the classical complement pathway, with subsequent pituitary damage and the recruitment of macrophages and other inflammatory cells leading to phagocytosis and enhanced antigen presentation (type II hypersensitivity reaction). The lymphocytes infiltration with ectopic lymphoid follicles near the pituitary cells (type IV hypersensitivity reaction) are, instead, a late event. Created in BioRender. La Sala, D. (2025) https://BioRender.com/d32a44. Abbreviations: CTLA-4: cytotoxic T-lymphocyte–associated antigen 4.

Figure 5

Postulated mechanism of action of PD1/PDL1 blocking antibodies on pituitary cells. It was supposed that at least a part of PD1/PDL1 antibodies-related hypophysitis is an enhancement of an already-present endogenous paraneoplastic form, evoked by an ectopic ACTH or POMC expression by tumor cells. Created in BioRender. La Sala, D. (2025) https://BioRender.com/r57p193. Abbreviations: DC: dendritic cell; ACTH: adrenocorticotropic hormone; POMC: pro-opiomelanocortin; CD8: cluster of differentiation 8; ICI: immune checkpoint inhibitor; PD1: programmed cell death protein 1; PDL1: programmed cell death ligand 1.