Bioengineering strategies to enhance BCG immunotherapy against bladder cancer

Bacillus Calmette–Guérin (BCG) remains the frontline immunotherapy for non–muscle-invasive bladder cancer (NMIBC), yet recurrence and non-response occur in over half of patients, highlighting the need for improved therapeutic strategies. Recent advances in bioengineering including genetic modification, synthetic biology, biomaterials, and delivery systems are expanding BCG from a traditional vaccine into a more versatile immunotherapeutic platform. In this review, we summarize the mechanisms of BCG-induced antitumor immunity and discuss current bioengineering strategies aimed at enhancing tumor interaction, innate immune activation, and modulation of the tumor immune microenvironment (TIME). We further highlight emerging approaches in delivery system design to improve intravesical retention and therapeutic efficacy. In addition, we discuss evolving perspectives on immune regulation in BCG therapy, including the potential contribution of type 2 immunity alongside canonical type 1 responses, as well as the role of trained immunity in sustaining antitumor effects. Finally, we outline key challenges for clinical translation and future directions toward more rational and precise BCG-based immunotherapy.