Kirtay, M.; Ispirjan, M.; Bonnard, B.; Bruggner, A.-L.; Boehringer, L.; Miessler, M.; Frey, N.; Leeper, N. J.; Jarr, K.-U.

Atherosclerosis is a chronic inflammatory disease and a leading cause of cardiovascular mortality worldwide. Disease progression is closely linked to defective efferocytosis, the impaired clearance of apoptotic cells, which drives necrotic core expansion and perpetuates arterial inflammation. Targeting the CD47-SIRP innate immune checkpoint, a dominant ''don't-eat-me'' signal, limits atherosclerosis in preclinical models and retrospective human studies. However, how pro-efferocytic intervention reshapes the immune landscape of established atherosclerotic lesions remains incompletely understood. Here, using single-cell transcriptomics, monocyte fate mapping, and functional analyses across complementary preventive and interventive murine atherosclerosis models, we demonstrate that CD47 blockade fundamentally reprograms the myeloid landscape of established lesions. Anti-CD47 therapy selectively suppresses inflammatory Ly6Chi monocyte recruitment and reduces local macrophage proliferation without altering overall plaque macrophage burden, indicating a qualitative rather than quantitative remodeling of the infiltrate. Concurrently, therapy enriches macrophage subsets bearing pro-efferocytic and macrophage survival-associated transcriptional programs, restoring defective apoptotic cell clearance in situ. Cross-species integration with an independent human coronary artery single-cell dataset identifies a conserved TREM2hi macrophage population that natively harbors the efferocytosis machinery reactivated by therapy in mice. Together, these findings demonstrate that innate immune checkpoint inhibition by CD47 blockade drives a coordinated reprogramming of monocyte-macrophage dynamics, simultaneously suppressing inflammatory influx and enriching efferocytic capacity. This dual mechanism advances our understanding of how pro-efferocytic therapies resolve vascular inflammation in atherosclerosis.