A self-gelling hemostatic powder boosting radiotherapy-elicited NK cell immunity to combat postoperative hepatocellular carcinoma relapse

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.