Nickan Research Institute Journal of Parathyroid Disease 2345-6558 14 1 2026 01 01 Calcitriol, PTHrP and beyond; pathophysiological pathways of hypercalcemia as an immune-related adverse event of checkpoint inhibitors e13323 e13323 10.34172/jpd.13323 EN Maryam Aghabozorgi https://orcid.org/0000-0002-4203-6584 Shahin Asgari https://orcid.org/0000-0002-5878-4608 Seyyed Hamidreza Motafakeran https://orcid.org/0009-0003-2719-8862 Ahmadreza Maghsoudi https://orcid.org/0000-0002-0173-1222 Journal Article 10.34172/jpd.13323 2026 04 07 2026 06 02 Hypercalcemia is a rare yet potentially life-threatening immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). While disease progression is the primary differential, distinct immune-mediated pathways necessitate specific clinical recognition. This review explores mechanisms involving calcitriol, parathyroid hormone-related protein (PTHrP), and inflammatory cascades. Classically, humoral hypercalcemia of malignancy involves tumor-secreted PTHrP. However, ICI-induced cases often exhibit suppressed parathyroid hormone with variable PTHrP, suggesting immune dysregulation rather than pure tumor burden. A significant pathway involves excessive calcitriol production, mirroring granulomatous diseases. Here, ICI-activated macrophages express 1-alpha-hydroxylase, converting vitamin D to its active form, thereby increasing intestinal calcium absorption and bone resorption. Additionally, PTHrP elevation may arise from immune-mediated tissue inflammation or sarcoid-like reactions triggered by T-cell activation rather than direct tumor secretion. Beyond these canonical pathways, cytokine release syndromes involving interleukin-6 and tumor necrosis factor-alpha can directly stimulate osteoclastogenesis by the RANKL pathway, accelerating bone breakdown. Direct immune infiltration into parathyroid glands or bone marrow might also disrupt calcium homeostasis. Distinguishing these mechanisms is critical, as management diverges from malignancy-associated hypercalcemia. Though, hydration and bisphosphonates are standard; however, corticosteroids are particularly effective for calcitriol-mediated or inflammatory mechanisms. Recognizing specific drivers prevents unnecessary treatments and ensures timely intervention. As ICI administration expands across oncology, clinicians must maintain high suspicion for these rare endocrine irAEs. Therefore, larger studies should define biomarkers to predict susceptibility and clarify molecular interactions. Eventually, elucidating these complex pathways ensures patient safety, preserving the therapeutic benefits of immunotherapy while effectively diminishing severe metabolic complications through optimal and targeted management strategies.