Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense

Chew Chai; Eliya Sultan; Souradeep R Sarkar; Lihan Zhong; Dania Nanes Sarfati; Orly Gershoni-Yahalom; Christine Jacobs-Wagner; Hawa Racine Thiam; Benyamin Rosental; Bo Wang

doi:10.1016/j.cell.2026.05.008

Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense

Cell. 2026 Jul 9;189(14):4342-4358.e8. doi: 10.1016/j.cell.2026.05.008. Epub 2026 Jun 2.

Authors

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
² Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Center for Regenerative Medicine and Stem Cells, Ben Gurion University of the Negev, Be'er Sheva 8410501, Israel.
³ Department of Biology, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Biology, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
⁶ Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Center for Regenerative Medicine and Stem Cells, Ben Gurion University of the Negev, Be'er Sheva 8410501, Israel. Electronic address: rosentab@post.bgu.ac.il.
⁷ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: wangbo@stanford.edu.

PMID: 42229422
DOI: 10.1016/j.cell.2026.05.008

Abstract

Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells-T cells, natural killer cells, and neutrophils. Here, we identify "ruptoblasts," a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, "ruptosis," triggered by activin, a multifunctional hormone acting as an inflammatory cytokine. Excessive activin-induced through protein injection, genetic chimerism, or bacterial infection-initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic and cell death mechanisms, the explosive nature of ruptosis relies on endoplasmic reticulum (ER)-derived calcium and cytoskeleton-dependent signal amplification. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.

Keywords: activin signaling; cell death/destruction; cytotoxicity; evolution of immune system; extreme cell biology; genetic chimeras; glandular/secretory cell types; hormonal surveillance; planarian.

MeSH terms

Activins / metabolism
Animals
Cell Death
Planarians* / cytology
Planarians* / immunology

Substances

Activins

Grants and funding

R35 GM138061/GM/NIGMS NIH HHS/United States