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  • Selective Prevention of Immune Checkpoint Inhibitor–Induced Hypophysitis Without Compromising Antitumor Immunity

  • Fatemeh Aghajani,1,*
    1. Shiraz University of Medical Sciences


  • Introduction: Immune checkpoint inhibitor (ICI)-induced hypophysitis, most often with anti-CTLA-4 therapy, can cause permanent anterior hypopituitarism and life-threatening adrenal crisis. Pituitary cells express CTLA-4, and CTLA-4 blockade induced pituitary inflammation and pituitary antibodies in mice, which suggests that prevention could target pituitary-specific mechanisms rather than T-cell activation as a whole. Whether hypophysitis can be prevented selectively, without weakening antitumor immunity, is unclear. We mapped the evidence on strategies to prevent ICI hypophysitis and on the risk information that selective prevention would depend on.
  • Methods: We conducted a scoping review using the Arksey and O'Malley framework and reported it according to PRISMA-ScR. PubMed, Europe PMC, the Cochrane Library and ClinicalTrials.gov were searched on 12 October 2026 for studies of hypophysitis or hypopituitarism in patients treated with ICIs that addressed prevention, prophylaxis, mitigation, risk factors, dose or antibody engineering. We included primary studies and reviews addressing prevention strategies, risk prediction, regimen-related risk, monitoring, or the relationship between endocrine toxicity and antitumor outcomes, and excluded case reports and general immune-related adverse event reviews. Studies were grouped as (A) risk factors and prediction, (B) regimen- and agent-related risk, (C) monitoring and early detection, (D) toxicity–efficacy coupling, and (E) conceptual preventive strategies. One reviewer screened the records and charted the data.
  • Results: The searches returned 92 records (PubMed 82, Europe PMC 0, Cochrane Library 0, ClinicalTrials.gov 10) and 13 studies were included: five in group A, three in B, two in C, one in D and two in E. No study tested an intervention to prevent hypophysitis, and ClinicalTrials.gov yielded no registered trial of hypophysitis prevention; related records were an observational study of endocrine immune-related adverse events and a trial of treatment, not prevention. All included primary studies were retrospective or observational. In group A, hypophysitis occurred in 8% to 13% of patients on ipilimumab, with male sex and older age as risk factors but not cumulative ipilimumab dose in one cohort; in another single-centre cohort none of 30 patients with prior systemic therapy developed hypophysitis versus 15 of 72 (17.2%) without it. A fall in free T4 and TSH index was predictive of later hypophysitis (P<0.001), plasma ACTH rose 1.72-fold before onset, and systematic cortisol screening in 75 patients on nivolumab found asymptomatic corticotropic insufficiency in 10.7%. In group B, hypophysitis was reported more often with combination therapy and anti-CTLA-4 than with other monotherapies in a FAERS analysis (reporting frequency 1.46%), and adrenal insufficiency occurred in 8% with relatlimab–nivolumab versus under 1% with nivolumab alone (P<0.001). In group C, baseline endocrine evaluation was absent in 22.3% and incomplete in 38.2% of 103 patients referred during ICI therapy, and central adrenal insufficiency raised the risk of an emergency (RR 3.29, 95% CI 1.33–8.08). In group D, ipilimumab hypophysitis was associated with longer median survival in one cohort (19.4 vs 8.8 months, P=0.05), and a review described immune toxicity and antitumor immunity as coupled but potentially separable. In group E, reviews proposed Fc engineering, conditionally activated antibodies and GLP-1 receptor agonists as possible approaches, one noting that current management is reactive and lacks preventive strategies.
  • Conclusion: We found no clinical evidence that hypophysitis can be prevented selectively; the available evidence concerns who is at risk and how to detect it earlier. Male sex, older age, CTLA-4-containing or combination regimens, and rising ACTH or falling thyroid indices could help define a high-risk group, but these findings come from small retrospective cohorts. Reports of better survival with hypophysitis mean that any prevention strategy must show it does not weaken antitumor immunity. Candidate approaches remain conceptual, and the next step is preclinical and prospective studies of pituitary-sparing strategies with tumor response as a co-primary outcome.
  • Keywords: immune checkpoint inhibitors; hypophysitis; prevention; CTLA-4; adrenal insufficiency

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