Hydrogels as advanced therapeutic delivery systems for improved cancer immunotherapy: current progress, challenges,...

Immunotherapy has emerged as a new clinical paradigm for cancer management, leveraging immunomodulation to enhance systemic antitumor responses. Despite its significant potency and distinct advantages, challenges such as limited patient response rates and immune-related toxicities persist. Although nanomaterial-based delivery systems have been explored to improve local drug retention within tumor tissues, the efficacy of systemic nanomaterial strategies is constrained by low bioavailability and poor tumor penetration. As innovative localized delivery systems, injectable hydrogels hold significant promise in overcoming these challenges. Capitalizing on their inherent biocompatibility, tailorable physicochemical characteristics, and biomimetic interactions with the extracellular matrix, these hydrogel systems can be engineered to achieve precise therapeutic delivery with enhanced stability and bioavailability. Additionally, they enable the combination of immunotherapy with complementary treatment modalities, such as chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and oncolytic virotherapy. This review begins by outlining the key steps of the cancer-immunity cycle, along with existing immunotherapeutic approaches and their inherent limitations. Then, we outline the design principles of hydrogel-based therapeutic delivery systems for cancer immunotherapy. Additionally, it summarizes recent advances in developing functional hydrogels for the localized delivery of small molecules, macromolecules, and immune cells to elicit robust antitumor immune responses. Moreover, we explore the potential benefits of hydrogel-based combination immunotherapy in enhancing therapeutic outcomes. Finally, we discuss the critical challenges and future perspectives for the clinical translation of hydrogel-based cancer immunotherapies.