Optimizing next-generation CAR-macrophages against solid tumors: challenges and potential strategies

Abstract Chimeric antigen receptor macrophage (CAR-M) therapy has emerged as a highly promising novel platform in solid tumor immunotherapy. Leveraging its inherent tumor-homing capacity, potent phagocytic function, and potential to remodel the tumor microenvironment (TME), CAR-M offers a new strategic approach to address the limitations faced by CAR-T therapy in solid tumors, such as poor infiltration and immunosuppression. Despite these mechanistic advantages, clinical outcomes with first-generation CAR-M constructs have been modest, largely due to their limited in vivo persistence and effector activity. In this review, we summarize the core challenges limiting the efficacy and clinical application of CAR-M, and provide an in-depth discussion of engineering strategies aimed at enhancing its anti-tumor activity through optimization of the CAR molecular structure. Beyond CAR-M engineering, we also outline recent advances in combining CAR-M with other therapeutic modalities and discussing their underlying synergistic mechanisms. Looking forward, we highlight next-generation CAR-M platforms, such as in vivo edited CAR-M and CAR-monocytes, which aim to simplify manufacturing, reduce costs, and enable more precise immune modulation. Although challenges remain in manufacturing, durability of response, and safety, continuous technological innovation and rational combination strategies are accelerating the translation of CAR-M therapy from proof-of-concept toward clinical application, holding promise for opening new avenues in solid tumor treatment.