Planarian flatworms possess 'ruptoblasts', a previously unknown glandular cytotoxic cell type that undergoes explosive cell death ('ruptosis') in response to activin, a hormone that also functions as an inflammatory cytokine, releasing diffusible agents that eliminate nearby cells, bacteria, and even mammalian cells within minutes through a calcium- and cytoskeleton-dependent mechanism distinct from all known cytotoxic processes. This activin-triggered immune surveillance system, which couples hormonal regulation with broad-spectrum cytotoxicity and appears evolutionarily conserved across basal bilaterians, reveals a fundamental immune strategy operating outside the hematopoietic lineage that can simultaneously eliminate hormone-secreting cells, stem cells, and pathogens.

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 that also acts 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 any 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 mechanisms, the explosive nature of ruptosis relies on intracellular calcium and dynamic cytoskeletal reorganization. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a widespread strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.