Rethinking CD47 an innate immune checkpoint and immunotherapeutic target in malaria pathogenesis: A narrative review.

Malaria remains a significant global health challenge, particularly in tropical regions, where high morbidity and mortality persist. The need for new therapeutic strategies remains urgent as increasing antimalarial drug resistance threatens treatment efficacy and highlights the need for innovative approaches that target not only the parasite but also host-pathogen interactions. While malaria immunology has traditionally focused on adaptive responses, including T-cell dysfunction, the role of innate immune checkpoints remains underexplored. Among these, CD47- a transmembrane protein best known for delivering a "don't-eat-me" signal to phagocytes has emerged as a potential therapeutic target. This concept is particularly relevant to malaria because Plasmodium infects red blood cells, whose survival and clearance are tightly regulated by CD47-SIRPα signalling. Emerging evidence suggests that CD47 contributes to the regulation of phagocytic clearance of infected red blood cells and may influence inflammatory responses associated with disease severity. Disruption of CD47-SIRPα signalling may enhance host phagocytic responses, promoting clearance of parasitized erythrocytes and potentially improving disease control. This review examines the immunopathological role of CD47 in malaria, evaluates its potential as a host-directed therapeutic target, and discusses the challenges and future directions for translating CD47-targeted strategies into clinical practice. CD47, therefore represents a promising but incompletely validated host-directed therapeutic target, with important translational gaps that must be addressed before clinical application.