Rationally engineered hydrogel-enabled modulation of tumor metabolism for enhanced antitumor immunotherapy

Immunotherapy has emerged as a paradigm-shift approach in oncology by harnessing the immune system to combat malignant tumors. Despite their promising therapeutic potential, most cancer patients fail to benefit from these treatments and often develop therapeutic resistance. Growing evidence indicates that environmental stress compels tumor cells to reprogram their metabolic pathways, enabling their survival under restrictive conditions. Additionally, tumor-derived metabolites reshape the function of immune cells and impair antitumor immune responses. Intercellular competition for nutrients between tumor and immune cells further compromises immune cell activity, thereby promoting immunosuppression. To overcome these metabolic barriers, hydrogel-based metabolic modulation strategies have recently been developed to intervene in various metabolic pathways and enhance immunotherapeutic efficacy. In this review, we first outline the metabolic features of the tumor microenvironment (TME), focusing on how metabolic reprogramming within the TME regulates immune cell activity and drives immunosuppression. We then summarize the latest progress in the development of multifunctional hydrogels designed for tumor metabolic reprogramming, highlighting their ability to achieve targeted immunometabolic modulation and enhanced antitumor immune responses. Finally, we critically discuss the current challenges and offer perspectives on the future development of advanced hydrogels targeting abnormal tumor metabolism for enhanced cancer immunotherapy and clinical implementation.