AbstractThe crosstalk between cancer cells and tumor associated macrophages (TAMs) within the tumor environment modulates tumor progression at all stages of cancer disease. TAMs are predominantly M2‐like polarized macrophages with tumor‐promoting activities. Nonetheless, they can be repolarized to tumoricidal M1‐like macrophages through macrophage colony stimulating factor 1 receptor inhibition (CSF1Ri). CSF1Ri is being explored as multifaced therapeutic approach to suppress TAMs tumor‐promoting functions and reduce cancer cell aggressiveness and viability. However, treatment with CSF1Ri results in significant TAMs death, thereby extinguishing the possibility of generating tumoricidal M1‐like macrophages. Immunotherapy has not only improved overall patient's survival in some cancer types, but also caused frequent off‐target toxicity. Approaches to balance efficacy versus toxicity are needed. Herein, a CSF1Ri‐loaded polymersomes (PMs) based delivery platform is developed to promote M2‐like macrophage repolarization. When testing in vitro on primary human monocyte‐derived macrophages (MDMs), CSF1Ri‐loaded PMs are preferentially taken up by M2‐like macrophages and enhance M2 to M1‐like macrophage repolarization while minimizing cytotoxicity in comparison to the free drug. When testing in a MDMs‐MDA‐MB‐231 breast cancer cell coculture model, CSF1Ri‐loaded PMs further retain their M2 to M1‐like macrophages polarization capacity. This CSF1Ri‐loaded PM‐based platform system represents a promising tool for macrophage‐based immunotherapy approaches.