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Highlights d CmAb-(IL10) 2 prolongs the half-life of IL-10 and minimizes its toxicity d Tumor-targeted IL-10 induces superior antitumor effects over nontargeted IL-10 d CmAb-(IL10) 2 prevents tumor-specific CD8 + TILs apoptosis through IL-10R on DCs d CmAb-(IL10) 2 overcomes resistance to immune checkpoint blockade

Herein, we report that genetically programmable fusion cellular vesicles (Fus‐CVs) displaying high‐affinity SIRPα variants and PD‐1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual‐blockade of CD47 and PD‐L1 with Fus‐CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T‐cell immunity. Moreover, the bispecific targeting design of Fus‐CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus‐CVs significantly improve overall survival of model animals by inhibiting post‐surgery tumor recurrence and metastasis. The Fus‐CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus‐CVs an attractive platform for multi‐targeting immune checkpoint blockade therapy.

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