Magnetically Guided Macrophage Immunobots Coordinate Iron-Metabolic Cascades and Immunogenic Ferroptosis for Tumor Immunotherapy

Zeng X(#)(1), Zhang Y(#)(2), Wu C(3), Duan Q(1), Fan M(2), Wang K(2), Cai S(3), Yasa IC(1)(2). Adoptive cell therapy (ACT) remains challenging in solid tumors, where poor tumor infiltration, metabolic heterogeneity, and an immunosuppressive tumor microenvironment (TME) constrain therapeutic efficacy. Here, we developed magnetically and metabolically programmed macrophage-based immune microrobots (immunobots) for active solid tumor immunotherapy. The immunobots are constructed by loading bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS)-modified Janus L10-FePt magnetic microrollers (LMRs), which function both as an external magnetic actuation unit and as biochemical regulators that program macrophages into an anti-tumor phenotype. Optimized LMR loading endows the immunobots with robust propulsion, retention under flow, and enhanced barrier penetration. LMRs drive M1-like polarization through LPS-induced inflammatory activation and FePt-derived labile iron-amplified oxidative stress, leading to altered iron homeostasis, elevated reactive oxygen species (ROS), and enhanced NF-κB signaling. Functionally, immunobots induce ferroptosis-associated immunogenic cell death (ICD) in tumor cells. In vivo, magnetically guided immunobots suppress tumor growth through coordinated remodeling of the tumor immune landscape, including tumor-associated macrophage (TAM) reprogramming, dendritic cell maturation, and enhanced CD8+ T cell activation. Collectively, this work establishes a magnetically guided and metabolically programmed microrobotic immunotherapy strategy for overcoming the physical, metabolic, and immunological barriers that limit cellular therapy in solid tumors.