Empowering macrophage to bridge innate and adaptive antitumor immunity through dual targeting of PCSK9 and innate immune checkpoint

However, despite robust enhancement of phagocytosis, such approaches often fail to generate durable antitumor immunity in solid tumors, highlighting a critical disconnect between innate immune activation and effective T cell responses. Here, we identify PCSK9 as an adaptive resistance factor induced by macrophage immune checkpoint blockade.

Tumor-derived PCSK9 promotes lysosomal degradation of MHC-I in macrophages, thereby impairing antigen cross-presentation and limiting CD8⁺ T cell priming. This previously unrecognized mechanism reveals how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this resistance, we engineered bispecific fusion proteins that concurrently target the CD47-SIRPα phagocytosis checkpoint and the PCSK9–MHC-I antigen presentation axis, among which SIRPαD1-αPCSK9 emerged as the optimal format.