Interoperability and reusability stand out as key factors that nurture the cost-efficiency, quality and expansion of Serious Game Ecosystems (SGE). This paper builds upon the blooming development of SGE and explores the new horizons SGE have brought for the enhancement of virtual engineering technologies and applications. The authors consider the integration of SGE into the Virtual Engineering and Systems (VES) workflow. SGEs are becoming an important component in enterprise agility and sustainability. In this context, the authors propose an Interoperability SGE Framework to facilitate reusability and interconnection within Game-based VES. The framework focuses on data, information, services, processes and organization interoperability and proposes a technical, cyber-physical, functional and organizational view. The integration of Cyber-Physical Systems with SGEs enable the development of new paradigms and game models including sensor and actuator integration, context sensing, smart environments and sensing objects.