Phosphatidylserine-binding molecules induce the formation of tumor cell-derived microvesicles for enhanced cancer immunotherapy

Abstract

Engineered microvesicles (MVs) derived from tumor cells, which preserve tumor-specific characteristics, have been extensively investigated as delivery systems or vaccines for cancer therapy. However, the negatively charged phosphatidylserine (PS) exposed on the surface of tumor-derived MVs can induce immune tolerance, evade immune responses and dampen immunotherapy effectiveness. Here, we report a functional molecule (FaZn) that not only actively targets PS exposed on tumor cell surfaces, inducing membrane blebbing and producing PS-blocked tumor cell-derived MVs (FaZn-MVs) but also directly generates stable PS-blocked MVs in situ within tumors, serving as an antigen repository. FaZn-MVs not only activate T-cell-mediated immune responses akin to a prophylactic vaccine, demonstrating robust protection against tumors but also suppress tumor growth in mice and offer long-term immune surveillance. Furthermore, when FaZn-MVs are combined with programmed death ligand 1 (PD-L1) inhibitors, they enhance potent antitumor immune responses, leading to significant improvements in survival and immune memory. This work establishes a promising method for the in vivo generation of personalized tumor microvesicle vaccines with PS blockade, revealing a promising strategy for activating antitumor immune responses. • Functional molecule with zinc (FaZn) is designed and synthesized. • The constructed FaZn could target phosphatidylserine (PS) exposed on the surface of tumor cells. • The constructed FaZn induce generation of PS-blocked tumor cell-derived microvesicles in situ within the tumor. • PS-blocked tumor cell-derived microvesicles induced by FaZn show potent anti-tumor immune responses.