Abstract
Liver resection represents a main curative treatment for patients with early-stage hepatocellular carcinoma (HCC), but there is a rather high incidence of postoperative HCC relapse, which severely shortens long-term survival time. Currently, no standard adjuvant strategies are available for preventing HCC relapse in clinical practice. Impaired natural killer (NK) cell anti-tumor immunity has been disclosed as a crucial root of HCC relapse, indicating that reinstating NK cell anti-tumor immunity may show promise to curb HCC relapse. Coincidently, mounting evidence shows that radiotherapy (RT) can trigger NK cell anti-tumor immunity, though its mechanisms have never been completely elucidated. Herein, we uncover that RT can induce immunogenic cell death and activate cGAS-STING pathway in HCC cells to elicit NK cell anti-tumor immunity. However, RT is also revealed to enhance autophagy and CD73 expression in HCC cells, as well as neutrophil extracellular traps (NETs) formation, which largely limits RT-induced activation of NK cell anti-tumor immunity. Therefore, a cocktail of autophagy inhibitor 3-methyladenine, CD73 inhibitor ARL 67156 trisodium and NETs lyase DNase I may sensitize RT to reinvigorate NK cell anti-tumor immunity and thus prevent HCC relapse postresection. To minimize therapy-related side effects, a nanocomposite powder encapsulating such a triple-drug cocktail is developed. This powder can rapidly form adhesive hydrogel in situ after applied to surgical margin, consequently fulfilling liver-localized sustained drug delivery. Importantly, it can sensitize RT to reinstate NK cell anti-tumor immunity to combat postoperative HCC relapse in Heap1-6-HCC murine model. Besides, this powder can also generate rapid hemostasis in rat and porcine models. Altogether, this work provides an innovative strategy to thwart postoperative HCC relapse and bleeding.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call