Efferocytosis inhibition enhances the anticancer immune response of hybrid cell membrane-coated nanoparticles.

The immunogenic cell death (ICD) of tumor cells generates abundant damage-associated molecular patterns (DAMPs) to induce efficient anti-tumor immune responses. However, dysregulated efferocytosis causes rapid clearance of DAMPs, thereby impeding immunotherapy progression. It has been revealed that the externalization of phosphatidylserine (PS) on apoptotic tumor cells serves as a key signal that drives efferocytosis imbalance. Here, we prepared a nanodrug HM-NP@SF&Xs, using hybrid membranes (HM) of macrophage and hepatocellular carcinoma (HCC) cell coated polymeric micelles incorporating sorafenib (SF) and Xkr8 siRNA. The HM coating prolongs blood circulating and enhances tumor targeting of nanodrugs, leading to efficient drug delivery into tumor. In addition, SF induces HCC apoptosis to trigger tumor ICD, thereby amplifying antitumor immune responses. Most importantly, the efferocytosis of SF-induced DAMPs can be effectively inhibited by Xkr8 siRNA via inhibition of PS exposure. Besides, systemic immune-related side effects of HCC cell membranes and Xkr8 siRNA are effectively reduced. In vitro and in vivo experiments demonstrated that the HM coated nanodrug elicits potent antitumor immune responses through inhibition of efferocytosis and release of inflammatory cytokines. The study provides an innovative strategy for drug delivery to HCC for enhanced immunotherapy against HCC. STATEMENT OF SIGNIFICANCE: Efferocytosis leads to the rapid clearance of immunogenic tumor debris, thereby suppressing anti-tumor immune responses. Herein, a hybrid membrane-coated nanodrug (HM-NP@SF&Xs) is developed to overcome efferocytosis-driven immunosuppression in hepatocellular carcinoma (HCC). By coating sorafenib and Xkr8 siRNA-loaded polymeric micelles with macrophage & tumor cell hybrid membrane, the platform achieves prolonged circulation and tumor-specific drug delivery. Sorafenib induces immunogenic cell death, while Xkr8 siRNA blocks phosphatidylserine externalization to inhibit efferocytosis of apoptotic tumor cells. This dual-action strategy amplifies antitumor immunity while reducing systemic side effects, offering a promising approach for enhanced cancer immunotherapy.