Lifespan‐Regulated CAR‐Macrophages from Myeloid Progenitors for Enhanced Colorectal Cancer Therapy

Adoptive cell therapies for solid tumors face persistent challenges from poor tumor infiltration and immunosuppressive microenvironment. To overcome these limitations, a clinically scalable platform is developed to generate chimeric antigen receptor macrophages (CAR-HMs) from tamoxifen-regulated immortalized Hoxb8-transduced myeloid progenitors, achieving >95% CAR transduction efficiency and 60-fold expansion within 10 days. Engineered with a colorectal cancer-specific anti-carcinoembryonic antigen (CEA) CAR, these FcγRI-CAR-HMs demonstrated potent tumoricidal activity (>80% CRC cell lysis in vitro), deep tissue penetration (>100 µm in 3D tumor spheroids), and significant therapeutic efficacy (≈89% tumor regression in vivo). Mechanistic studies demonstrated that FcγRI-CAR-HMs remodeled the tumor microenvironment through direct tumor phagocytosis, T cells recruitment and activation, and synergistic enhancement of anti-PD-1 therapy in colorectal cancer models, while an integrated inducible caspase-9 (iCas9) suicide switch ensured safety without compromising long-term persistence. This progenitors-based platform not only addresses critical manufacturing challenges but also unlocks the full therapeutic potential of CAR-macrophages, whose unique ability to synergize with checkpoint inhibitors provides a transformative approach for treatment-refractory solid tumors.