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

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 Ca2+ 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 Ca2+ within the tumor environment and DMA continuously prevents cellular Ca2+ influx, suppressing Ca2+-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-gamma 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

Automated summary

A PD-L1 checkpoint-regulatable immune niche has been created by an injectable hydrogel, reprogramming PD-L1 of both tumor cells and circulating exosomes, offering an innovative approach to cancer immunotherapy.