IL-21 promotes the anti-tumor effect of anti-CD47 chimeric antigen receptor macrophages in ovarian cancer

Macrophages play a key role in immunity against solid tumors. However, their development and clinical applications are limited by their difficult-to-transfect nature, low proliferative capacity, and easily changing polarization states. The combination of chimeric antigen receptor (CAR) technology with macrophages to form chimeric antigen receptor macrophages (CAR-Ms) is an emerging strategy for adoptive cell therapy. In our previous study, we confirmed that anti-CD47 CAR-Ms have potential for ovarian cancer treatment. Here, we demonstrated that the introduction of IL-21 significantly increases the tumor-suppressive effect of anti-CD47 CAR-Ms against ovarian cancer. Specifically, IL-21-modified CAR-Ms with second-generation CARs targeting CD47 showed potent tumor cell-killing activity, both in vitro and in vivo, through direct and indirect pathways (direct phagocytosis and activation of cytotoxic T lymphocytes). In addition, an IL-21 modification significantly enhanced the tumor microenvironmental regulation of immunosuppression mediated by anti-CD47 CAR-Ms in vivo, thereby improving their therapeutic efficacy in a mouse model of ovarian cancer, without any obvious adverse effects. Taken together, these results suggest that anti-CD47 CAR-Ms combined with IL-21 is a promising treatment strategy for ovarian cancer.