Fighting cancer smarter: Using hydrogel delivery systems to target chemokines

Chemokines organize immune cell locomotion and trafficking in the tumor milieu, exerting dual roles by either boosting antitumor immunity (e.g., CXCL9/10/11 recruit effector T-cells) or promoting tumor progression (e.g., CCL2 supports immunosuppressive myeloid cells). Short half-lives, off-target effects, and tumor microenvironment (TME) barriers such as hypoxia and acidity hinder systemic administration of chemokines. Hydrogel-based delivery systems provide a biocompatible and tunable platform for controlled, localized chemokine release, thereby improving cargo stability and facilitating effector T-cell infiltration. Preclinical evidence also suggests that hydrogel-delivered chemokines may enhance responses to immune checkpoint inhibitors (ICIs), offering improved tumor regression compared to ICIs alone. Importantly, this review addresses not only therapeutic potential but also safety considerations, including local tissue toxicity, immune overstimulation, and translational challenges. Collectively, the article synthesizes chemokine biology, hydrogel-based chemokine delivery strategies, and preclinical outcomes, while outlining key hurdles and future directions for optimizing chemokine-focused cancer immunotherapy. However, clinical evidence remains limited, underscoring the need for close monitoring of immune-related adverse events (irAEs) and long-term effects on immune homeostasis.