Advances in Tumor-Derived Exosomal Non-Coding RNAs Regulating M2 Macrophage Polarization: Molecular Mechanisms and Signaling Pathway

Abstract

Background: Cancer persists as a leading cause of global mortality, largely due to the immunosuppressive tumor microenvironment (TME) that facilitates tumor progression and therapy resistance. M2 macrophages dominate this immunosuppressive landscape, and emerging evidence highlights tumor-derived exosomes (TEXs) as critical mediators of macrophage M2 polarization via delivery of noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs. These TEX-ncRNA networks activate key signaling pathways (e.g., JAK/STAT, PI3K/AKT, NF-κB) to sustain immunosuppression and pro-tumorigenic responses. Understanding the molecular intricacies of TEX-driven M2 polarization is essential for advancing immunotherapeutic strategies. Methods: This review systematically analyzes literature (2019–2024, from PubMed and Web of Science) on the molecular mechanisms by which TEX-derived ncRNAs drive M2 polarization and their interplay with immunotherapies. Results and Conclusion: This review contains 142 citations, 60 of which are detailed examples of this mechanism. Our analysis of the literature shows that TEXs deliver specific ncRNAs to macrophages, reprogramming them toward an M2 phenotype via pathways such as PTEN/PI3Kγ, Wnt/β-catenin, and STAT3. This polarization amplifies immunosuppressive factor secretion and promotes tumor metastasis, chemoresistance, and immune evasion. These insights provide a theoretical foundation for novel TME-targeted therapies, potentially improving outcomes in refractory cancers.