Space Radiation Sparks Hidden Cancer Risks: The Bystander Effect Unveiled

High-energy space radiation poses a substantial carcinogenic risk to astronauts during deep space missions. However, the mechanistic basis for this risk remains poorly defined. This study uncovers a novel oxidative stress (OS)-driven mechanism by which low-dose 56 Fe-ion exposure induces tumorigenic transformation. We demonstrate that irradiated endothelial cells (ECs) initiate a self-sustaining nuclear factor κB–tumor necrosis factor-α positive feedback cycle, which perpetuates intracellular reactive oxygen species generation and proinflammatory signaling. This positive feedback cycle not only maintains OS in irradiated ECs but also drives paracrine-mediated reactive oxygen species production and DNA damage in nontargeted bystander epithelial cells (EPs). Critically, this bystander response promotes nuclear factor κB-dependent survival signaling, including upregulation of B cell lymphoma 2, myeloid cell leukemia 1, survivin, and glycogen synthase kinase-3β, leading to tumorigenic gain of function. Crucially, we validated the tumorigenic gain of function in vivo in 8 independent mouse models with (a) nontumorigenic mammary EPs exposed 56 Fe ions or (b) cocultured with ECs exposed to 56 Fe ions; (c) directly irradiated or (d) bystander breast cancer cells cocultured with irradiated ECs; (e) nontumorigenic human bronchial EPs directly exposed to 56 Fe ion or (f) cocultured with ECs exposed to 56 Fe ion; and (g) directly irradiated or (h) bystander lung cancer cells cocultured with irradiated ECs. Tumor formation was observed in nontumorigenic mammary and bronchial EPs and heightened in cancer cell lines, confirming the transmissibility and amplification of high-energy radiation-induced OS effects. Our findings provide novel mechanistic insight into delayed effects of space radiation, highlighting OS as a central mediator of space-radiation-induced carcinogenesis, and offer a foundation for developing countermeasures for long-term cancer risks in astronauts.