Polarization-Specific Macrophage-Derived Extracellular Vesicles: Molecular Cargo, Tumor Microenvironment Remodeling, and Therapeutic Opportunities

Extracellular vesicles (EVs) derived from macrophages have emerged as critical regulators of tumor progression by functioning as polarization-dependent carriers of bioactive molecular information. Rather than acting as passive byproducts, macrophage-derived EVs reflect the activation state of their parent cells and actively reprogram tumor behavior and the tumor microenvironment. In this review, we propose a conceptual framework in which macrophage-derived EVs serve as information hubs that link macrophage polarization, selective cargo loading, and coordinated modulation of tumor and immune cell phenotypes. EVs released from classically activated (M1) macrophages predominantly convey tumor-suppressive signals, including specific noncoding RNAs and immunomodulatory proteins, thereby inhibiting tumor proliferation, invasion, immune evasion, and therapeutic resistance while reinforcing anti-tumor immunity. In contrast, EVs derived from alternatively activated (M2) macrophages deliver a coherent pro-tumor program that integrates epithelial-mesenchymal transition, metabolic reprogramming, stemness maintenance, ferroptosis resistance, immune suppression, and therapy tolerance across multiple cancer types. We systematically summarize the emerging mechanisms governing polarization-dependent cargo selection, including RNA-binding protein-mediated sorting, metabolic and signaling pathway control, and EV biogenesis regulation. In addition, this review highlights the translational implications of macrophage-derived EVs as engineering-ready platforms. We discuss strategies to enhance the therapeutic utility of M1 EVs through cargo engineering and surface functionalization, as well as approaches to disrupt, reprogram, or selectively block M2 EV-mediated oncogenic information flow. Collectively, this work advances a unifying molecular and translational perspective, positioning macrophage-derived EVs as actionable targets and tools for precision modulation of the tumor microenvironment in cancer diagnosis and therapy.