Today there are numerous Factories of the Future initiatives delivering different Industry 4.0 applications to manufacturing industry supply chains. However, in the future, Factory of the Future is not going to be a simple manufacturing asset, nor a sum of isolated assets. Instead, it will comprise a network of factories, which is considered in a System of Systems approach. The current challenge is to propose novel architectures, technologies and methodologies to optimize the level of efficiency and security of this System of Systems in a context where every step towards digitization exposes the manufacturing process to a widening array of cyber threats. This paper discusses about the management of cyber threats in System of Systems operations and supply chains. The next generation System of Systems are using different technologies with the combination of human aspects from workers, managers, entrepreneurs and decision makers. In addition, economically there are limitations on how much to invest on different technologies and human aspects. In addition, monetary and financial flows are under the burden of cyber risks. This study will therefore embrace the technical, economic and human dimensions at once. This study is based on a European-wide multi-national research project, the aim of which is to define – through different use-cases – the preventive and reactive capabilities to address cyber and physical threats and safety concerns in System of Systems. The study indicates different cyber challenges related to the future manufacturing business and operational models, with a special attention on “as-a-service” business model. The paper also indicates initial managerial and practical views on the management of cyber threats in future business models.