In vivo CAR-M therapy: advancing precision delivery and programmable immune remodeling

In recent years, chimeric antigen receptor-macrophages (CAR-Ms) have emerged as a pivotal branch of adoptive cell therapy. They are distinguished by their innate tumor infiltration capacity, phagocytic activity, and immunomodulatory functions, attributes that render them particularly promising for the treatment of solid tumors and non-malignant diseases. Nevertheless, the widespread clinical translation of CAR-M therapy has been constrained by the complexity, high cost, and potential genotoxicity inherent to traditional ex vivo manufacturing processes. As a transformative paradigm, in vivo CAR-M therapy bypasses these limitations by directly delivering CAR-encoding sequences to myeloid cells using advanced platforms such as viral vectors, lipid nanoparticles, extracellular vesicles, or biomaterials. This strategy enables the in situ genetic programming and functional remodeling of macrophages, thereby streamlining therapeutic workflows, reducing production costs, and broadening patient accessibility. This review systematically summarizes recent advances in in vivo CAR-M therapy, focusing on its applications across diverse solid tumors and non-malignant conditions. We compare in vivo engineering strategies with conventional adoptive CAR-M approaches from both mechanistic and translational perspectives and critically examine key challenges, including delivery specificity, immunological safety, and controllability of transgene expression. Collectively, in vivo CAR-M represents a paradigm shift from ex vivo manufacturing toward in vivo cellular programming, offering a more accessible and scalable next-generation immunotherapeutic platform for solid tumors and inflammation-related diseases.