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 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‐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

Targeted delivery of quercetin by biotinylated mixed micelles for non-small cell lung cancer treatment

“…In spite of the excellent antitumor effects, low water solubility, poor metabolic stability and bioavailability, short half-life and poor tumor targeting capability have been proven almost to be an insurmountable obstacle for clinical translations of Que (Dabeek & Marra, 2019 ). Recent progresses in nanotechnology offer more possibilities to overcome these drawbacks of drugs themselves, which can efficiently encapsulate them and ameliorate their pharmacokinetics and pharmacodynamic profiles (Zhou et al., 2020 ; Li et al., 2021a,b ; Zhang et al., 2022 ). Interestingly, nanoparticles are capable of passively accumulating into tumor sites as a result of incomplete vessels and lymphatic blockage termed as enhanced permeability and retention (EPR) effect (Fang et al., 2011 ).…”

Injectable Hydrogel as a Unique Platform for Antitumor Therapy Targeting Immunosuppressive Tumor Microenvironment

“…reported a cancer cell membrane-derived hydrogel scaffold loaded with Ca 2+ channel inhibitor dimethyl amiloride (DMA) and cyclin-dependent kinase 5 inhibitor roscovitine for cancer treatment. In this system, cancer cell membrane, DMA and roscovitine were chosen with the aim of creating an antigen depot, suppressing Ca 2+ -governed exosome secretion and down-regulating tumor cell PD-L1 expression, respectively ( 52 ).…”

“…Li et al reported a cancer cell membrane-derived hydrogel scaffold loaded with Ca 2+ channel inhibitor dimethyl amiloride (DMA) and cyclin-dependent kinase 5 inhibitor roscovitine for cancer treatment. In this system, cancer cell membrane, DMA and roscovitine were chosen with the aim of creating an antigen depot, suppressing Ca 2+ -governed exosome secretion and downregulating tumor cell PD-L1 expression, respectively (52). CTLA-4 is expressed on activated Th1 cells and CTLs, and binds to co-stimulatory molecules CD80 and CD86 of antigenpresenting cells, thereby inhibiting the activation and proliferation of T cells (53).…”

Three-dimensional (3D) scaffolds as powerful weapons for tumor immunotherapy

“…Cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are the most two characterized. These molecules are self-tolerant under normal physiological contexts but easily powerless by malignancy [ 38 , 39 ]. Cancer cells aim to bind them with self-expressed specific receptors so that antitumor signalling and immune attack will be prevented.…”