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Simple Summary: AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs in healthy adults but is also re-expressed in ovarian, colorectal and lung cancers. In this context, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody, currently in clinical trial. Preliminary data suggest that murlentamab anti-tumor activity involves immune response activation. Thus, in vitro experiments were performed to precisely characterize the murlentamab effect on the human immune system. We show that murlentamab treatment is associated with evidences of innate and adaptive immune cell activation in cancer patient samples. Moreover, we demonstrate that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells promotes a polarization switch of both naïve and tumor-associated macrophages towards an anti-tumor M1-like phenotype. Our work also supports that, through macrophage reeducation, murlentamab activates an anti-tumor adaptive immune response. Finally, the combination of murlentamab with pembrolizumab confirmed novel clinical perspectives of murlentamab association with checkpoint inhibitors and other immuno-modulators. AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives. [ABSTRACT FROM AUTHOR]