Ferroptosis, an unusual nonapoptotic cell death caused by iron-dependent accumulation of lipid peroxide, enables flexible design of antitumor platform. Specifically, as a positive role, ferroptosis can induce immune response accompanied...

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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

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Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca 2+ cycling in cardiomyocytes have been recognized in some cardiovascular diseases, their roles in RV failure secondary to pulmonary arterial hypertension require further investigation. In a monocrotaline-induced rat model of pulmonary arterial hypertension, the RV remodeling process was divided into normal, compensated, and decompensated stages according to the hemodynamic and morphological parameters. In both compensated and decompensated stages, significant diastolic SR Ca 2+ leakage was detected along with reduced intracellular Ca 2+ transient amplitude and SR Ca 2+ contents in RV myocytes. RyR2 protein levels decreased progressively during the process, and the thiol oxidation proportions of RyR2 were higher in compensated and decompensated stages than in normal stage. Inhibition of RyR2 oxidation by dithiothreitol or repairing RyR2 directly by dantrolene could restore Ca 2+ homeostasis in RV myocytes. Daily intraperitoneal injection of dantrolene delayed decompensation progression and significantly improved the survival rate of pulmonary hypertension rats in decompensated stage (79.3% versus 55.9%; P =0.026). Our findings suggest that diastolic SR Ca 2+ leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca 2+ leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.