Checkpoint-insulated triple-signal artificial antigen-presenting cells drive antigen relay and systemic antitumor immunity.

Abstract

Dendritic cell (DC) vaccines offer professional antigen presentation but are often limited by suboptimal trafficking to lymphoid tissues, whereas whole tumor cell vaccines preserve antigenic diversity yet frequently lack coordinated activation cues for efficient T cell priming. Here, we report OncoAPC, an inactivated artificial antigen-presenting cell designed around a triple-signal priming logic: MHC-I-mediated antigen presentation (signal 1), CD80-mediated costimulation (signal 2) with checkpoint-insulating capacity, and incorporated IL-12 (signal 3). Mechanistically, OncoAPC directly activated T cells while partially insulating against PD-1 suppression through <i>cis</i> CD80:PD-L1 interactions and simultaneously engaged endogenous DCs to relay tumor antigens via cross-dressing and amplify lymphoid priming. Across multiple tumor models, OncoAPC showed broad therapeutic activity, including marked suppression of metastatic tumor burden and substantial control of established tumors, outperforming conventional DC vaccination. It further retained efficacy beyond the MC38 backbone and remained active when generated from human tumor cells or excised tumor-derived material. These findings establish OncoAPC as a scalable, broad-spectrum cancer vaccine platform that integrates antigenic diversity with DC-like functional precision.