Stanniocalcin 1 at the nexus of calcium homeostasis, IGF signaling, and cancer immunity

The textbook view of the regulation of calcium homeostasis centers on parathyroid hormone, calcitriol, and calcitonin. While this paradigm has long dominated the field, it represents only part of a broader evolutionary and physiological landscape. This article focuses on Stanniocalcin 1 (STC1), a calciotropic hormone originally discovered in bony fish. Since its discovery in the 1970s, our understanding of STC1 has evolved from a "fish-specific" hormone to a member of a multifunctional glycoprotein family with deep roots in metazoan evolution. Recent studies in zebrafish show that STC1 inhibits calcium uptake through two mechanisms: it reduces TRPV6-dependent calcium influx and limits the proliferation of calcium-transporting ionocytes. Mechanistically, STC1 suppresses local insulin-like growth factor (IGF) signaling by binding pappalysin-family IGF-binding protein (IGFBP) proteases, thereby modulating IGFBP processing and downstream IGF activity. This STC1-Pappalysin-IGFBP-IGF axis has recently been positioned as a central node in an organ-brain communication pathway that links calcium uptake to brain function and animal behavior. In humans and other mammals, STC1 is expressed in many tissues locally and exerts local actions in a paracrine fashion. Dysregulation of STC1 expression has been associated with chronic kidney diseases and multiple cancer types. Recent studies have uncovered a novel role for STC1 in tumor immune evasion as a phagocytosis checkpoint and a "don't eat me" signal. This review integrates recent findings on the multifunctional roles of STC1 in regulating calcium homeostasis, IGF signaling, and cancer immunity, and to highlight the therapeutic potential of targeting STC1 in kidney diseases and cancer immunotherapy.