As knowledge-driven growth becomes central to long-term economic sustainability, universities are increasingly expected to expand their role beyond teaching and research to support innovation, entrepreneurship, and resilient regional development. This study investigates how entrepreneurial universities emerge and evolve within China’s innovation-driven development strategy, using Shenzhen as an in-depth regional case. Building on the Triple, Quadruple, and Quintuple Helix frameworks, the study adopts a mixed-methods design that integrates policy analysis, original survey data, and semi-structured interviews with key actors from universities, industry, government, and venture capital. This approach enables a systematic examination of governance arrangements, collaboration patterns, and institutional dynamics shaping sustainable innovation capacity in an industry-led innovation ecosystem. The findings reveal that Shenzhen’s innovation system is characterized by industry-driven technological upgrading, state-enabled entrepreneurial governance, and adaptive university transformation, resulting in a hybrid Helix configuration that departs from conventional Western university-centered models. The study identifies distinctive pathways through which universities in late-developing contexts build entrepreneurial capacity despite limited traditional research infrastructure, including boundary-spanning partnerships, practice-oriented knowledge transfer, and market-responsive organizational reforms. By theorizing novel coordination mechanisms among Helix actors, this research advances scholarship on entrepreneurial universities and innovation systems, while offering policy-relevant insights for strengthening sustainable university entrepreneurship, multi-actor collaboration, and long-term regional innovation resilience in emerging economies.