CELL INTELLIGENCE · 肿瘤细胞治疗研究

The SIRPα-CD47 "don't eat me" checkpoint axis plays a critical role in shaping antitumor activities of macrophages within the tumor microenvironment (TME). However, targeting this axis with anti-CD47 antibodies to enhance antitumor responses in clinical trials has been challenging. Here, we demonstrated that SIRPA -knockout (KO) iPSC-derived macrophages (iMacs) exhibit superior antitumor activity against various CD47-expressing tumors in vitro when combined with cancer-targeted monoclonal antibodies (mAbs) or chimeric antigen receptors (CARs). Moreover, SIRPA -KO protected macrophages from mAb- and CAR-driven hypophagia, enabling efficient tumoricidal effects even after serial tumor exposures. Retention of phagocytic activities in SIRPA -KO iMacs was associated with heightened surface expression of Fc receptors and GD2-CAR compared to their SIRPA -expressing counterparts. Despite the powerful impact of SIRPA -KO on iMac antitumor activities in vitro , only modest efficacy was observed in human xenograft mouse models of SK-OV3 ovarian carcinoma and CHLA-163 neuroblastoma treated with mAb or CAR-iMac therapy, indicating further engineering or combinatorial therapeutic strategies are needed for potent in vivo antitumor efficacy. Together, these findings identify SIRPα as a regulator in macrophage hypophagia and underscore the advantages of using SIRPA -KO macrophage therapeutic strategies to modulate the SIRPα-CD47 checkpoint to unleash macrophage antitumor activity within the TME.