With the anticipated growth in air traffic complexity in the coming years, future civil aviation transportation system (CATS) is transforming into a complex cyber-physical-social system, surpassing all previous experiences in the history of civil aviation safety management. Therefore, a new safety concept based on a system-of-systems (SoS) perspective is proposed for the next-generation aviation. This article begins by elucidating the complexity of existing aviation risks and emphasizing the necessity for an updated safety concept. It then presents the challenges of current safety management and potential solutions from the new SoS perspective. To address future risks, the concept of SoS safety is introduced with the inspiration of the human immune system in terms of capability, logic, and architecture, which can serve as a guiding framework and methodology for safety engineering in complex large-scale CATS. This concept indicates the transition from “process and outcome-oriented" to “capability-oriented" intelligent safety management. Our research highlights the development directions and potential technological areas that need to be addressed at different stages of SoS safety. The integration of SoS design and operation through rapid iterations enabled by artificial intelligence (AI) will ultimately achieve endogenous SoS safety.