FcγR-driven chimeric receptor T cells in cancer therapy: a novel frontier in antibody-guided immunotherapy

This review article looks at a novel and flexible framework in adaptive cell treatment that enhances tumor targeting using Fc gamma receptor (FcγR)-based chimeric receptors. Though chimeric antigen receptor (CAR) T cell therapies have shown notable effectiveness in hematologic malignancies, their efficiency against solid tumors is limited by tumor heterogeneity, immunosuppressive tumor microenvironments (TMEs), and off-target toxicities. By replacing the conventional scFv domain with the extracellular domains of FcγRs—including CD16a, CD32a, or CD64a—FcγR-CR T cells provide a unique method allowing T cells to be steered by monoclonal antibodies (mAbs) targeting several tumor-associated antigens (TAAs). Emphasizing their advantages in flexibility, reversibility, and compatibility with present antibody therapy, the review clarifies the mechanisms of action, preclinical developments, and clinical promise of FcγR-CR T cells. Future directions include increasing specificity by means of affinity-engineered FcγRs and Fc-modified monoclonal antibodies, generating universal allogeneic FcγR-CR T cells for immediate use, using regulatable expression systems to improve safety, and combining these engineered cells with immune checkpoint inhibitors or metabolic modulators to overcome tumor microenvironment resistance. Overall, FcγR-CR T cells offer a hopeful next-generation immunotherapeutic approach able to handle the current CAR T cell constraints and change precision oncology, particularly for aggressive and treatment-resistant solid cancers.