CAR-macrophage therapy: a novel strategy to overcome antimalarial drug resistance by targeting PfEMP1-mediated adhesion

Antimalarial drug resistance poses a critical threat to global malaria control efforts. Despite the continuous development of novel antimalarial compounds, the emergence of drug resistance remains inevitable, highlighting the urgent need for paradigm-shifting therapeutic approaches. Here, we propose an innovative chimeric antigen receptor-macrophage (CAR-M) cell therapy that circumvents traditional small-molecule limitations by harnessing the innate phagocytic capacity of macrophages. This strategy exploits the specific adhesive interactions between Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host receptors (CD36, ICAM-1/CD54, EPCR/CD201) to enable targeted recognition and elimination of infected erythrocytes. By engineering macrophages with chimeric antigen receptors directed against PfEMP1-binding domains, we establish a cell-based immunotherapy platform that provides sustained anti-parasitic activity independent of conventional drug susceptibility profiles. This approach represents a fundamental departure from chemical-based interventions by providing a potentially resistance-proof therapeutic modality for drug-resistant malaria.