Synthetic antibody mimics with the targeting and effector functions of natural antibodies hold great potential for cancer immunotherapy. However, current synthetic antibody mimics lack the ability of allostery as natural antibodies which is the structural basis for antibodies to achieve powerful therapeutic efficiency. Here, the mixed-shell polymeric micelle was used to construct a novel allosteric synthetic antibody (Allo-SyAb) that is capable of spatiotemporally activating in response to tumor microenvironment for cancer immunotherapy. Allo-SyAb presents a "silent" state in the blood circulation to avoid non-targeted activation which significantly prolongs blood circulation and enhances tumor accumulation. Once Allo-SyAb reaches the tumor microenvi-ronment, it undergoes a pH-responsive reversible allosteric effect and rapidly switches to the "activated" state to effectively promote antigen-presenting cells (APCs) mediated antitumor immune activation. We believe the system of allosteric synthetic antibody presents an efficient strategy for improved cancer immunotherapy.