A Checkpoint‐Regulatable Immune Niche Created by Injectable Hydrogel for Tumor Therapy

Abstract Current programmed death‐1 ligand (PD‐L1)‐based therapy focuses on local tumors. However, circulating exosomal PD‐L1 possesses inherent anti‐PD‐L1 blockade resistance and dominates tumor metastasis, playing a critical role in systemic immunosuppression. Therefore, the efficacy of immune checkpoint therapy depends on simultaneously decreasing tumoral and circulating exosomal PD‐L1. However, such therapeutic platforms have never been reported so far. Herein, a PD‐L1 checkpoint‐regulatable immune niche created by an injectable hydrogel is reported to reprogram PD‐L1 of both tumor and circulating exosomes. Oxidized sodium alginate‐armored tumor membrane vesicle (O‐TMV) as a gelator, with Ca 2+ channel inhibitor dimethyl amiloride (DMA) and cyclin‐dependent kinase 5 (Cdk5) inhibitor roscovitine formed hydrogel (O‐TMV@DR) in vivo, work as an antigen depot to create an immune niche. O‐TMV chelates Ca 2+ within the tumor environment and DMA continuously prevents cellular Ca 2+ influx, suppressing Ca 2+ ‐governed exosome secretion with decreased exosome number. Roscovitine not only down‐regulates tumor cell PD‐L1 expression along with decreasing exosomal PD‐L1 expression inherited from parental tumor cells via a genetic blockade effect, but also blunts the cascade connection between PD‐L1 up‐regulation and interferon‐γ stimulation, achieving down‐regulated PD‐L1 expression in both tumor cells and exosomes. Therefore, a full‐scale reprogramming of both tumoral PD‐L1 and exosomal PD‐L1 is achieved, offering an innovative immune checkpoint‐regulatable cancer immunotherapy