Advanced engineering of hydrogel platforms for cancer immunotherapy via distinct administration routes

Cancer immunotherapy has transformed cancer treatment by harnessing the host immune system to achieve durable and systemic antitumor responses; however, its clinical efficacy remains limited by insufficient immune activation and inadequate spatiotemporal control of therapeutics. Hydrogels have recently emerged as versatile platforms for cancer immunotherapy owing to their tunable networks, programmable release profiles, and adaptability to diverse administration routes. Nevertheless, existing reviews mainly categorize hydrogel systems according to material composition or immunological mechanism, often overlooking the administration route as a key determinant of drug distribution, immune activation, and therapeutic outcome. Here, we provide the first comprehensive and administration route-oriented overview of hydrogel-based delivery strategies for cancer immunotherapy. We summarize how hydrogels address distinct physiological and immunological barriers associated with intratumoral, peritumoral, postsurgical, intraperitoneal, intravenous, subcutaneous, oral, and intranasal administration. For each route, we discuss hydrogel design principles, representative systems, controlled payload release, and their roles in reshaping the tumor microenvironment, enhancing antigen presentation, promoting cytotoxic T cell responses, and coordinating local and systemic immunity. Finally, we outline future directions for administration route-guided hydrogel immunotherapy, emphasizing the importance of aligning hydrogel size, dynamics, and functionality with administration route-specific immune contexts. We further discuss the current progress in clinical translation and clinical trials of hydrogel-based cancer immunotherapy, highlighting emerging opportunities and remaining challenges for their future clinical application. This administration route-based framework provides a new perspective for designing personalized and multifunctional hydrogel systems for enhanced cancer immunotherapy.