Integrated sensing and communication (ISAC) enables radio systems to simultaneously sense and communicate with their environment. This paper, developed within the Hexa-X-II project funded by the European Union, presents a comprehensive cross-layer vision for ISAC in 6G networks, integrating insights from physical-layer design, hardware architectures, AI-driven intelligence, and protocol-level innovations. We begin by revisiting the foundational principles of ISAC, highlighting synergies and trade-offs between sensing and communication across different integration levels. Enabling technologies (such as multiband operation, massive and distributed MIMO, non-terrestrial networks, reconfigurable intelligent surfaces, and machine learning) are analyzed in conjunction with hardware considerations including waveform design, synchronization, and full-duplex operation. To bridge implementation and system-level evaluation, we introduce a quantitative cross-layer framework linking design parameters to key performance and value indicators. By synthesizing perspectives from both academia and industry, this paper outlines how deeply integrated ISAC can transform 6G into a programmable and context-aware platform supporting applications from reliable wireless access to autonomous mobility and digital twinning.