Decoding the Tumor Microenvironment: Exosome-Mediated Macrophage Polarization and Therapeutic Frontiers

作者：Yilin Li, Jiaqi You, Zifang Zou, Guanghao Sun, Yuqing Shi, Yanbin Sun, Shun Xu, Xin Zhang · 发表于：International Journal of Biological Sciences · 年份：2025 · DOI：10.7150/ijbs.114222 · 被引用次数：38 · 研究领域：Extracellular vesicles in disease

The tumor microenvironment (TME) is dynamically shaped by interactions between tumor cells, immune cells, and stromal components.Among these, tumor-associated macrophages (TAMs) play dual roles in tumor progression.Exosomes are key mediators of intercellular communication and are crucial for modulating macrophage polarization.This review systematically summarizes the role of HIF-1α as the central regulator of tumor-derived exosomes under hypoxic conditions.Under endoplasmic reticulum stress (ERS), the STAT3 and PI3K/AKT/mTOR pathways activation is mediated by the inactivation of the Hsp90/Hippo pathway, which induces the expression of LncRNA HMMR-AS1 and specific miRNAs (e.g., miR-1246, let-7a, miR-301a-3p, etc.).Furthermore, the IRE1/PERK pathway regulates exosome secretion by carrying miR-23a-3p and miR-27a-3p or directly delivering PD-L1 protein, thus activating the PI3K/AKT pathway, inhibiting PTEN, and upregulating PD-L1 expression as well as increasing the M2 polarization of macrophages.This study also summarized the important matrices of exosomes' involvement in the interaction between tumor cells and macrophages in different systemic malignant tumors.Moreover, the bidirectional crosstalk between TAM-derived exosomes and other TME components (e.g., CD8+ T cells, fibroblasts) was also evaluated, which indicated their roles in immune evasion and metastasis.Further, engineering strategies, such as receptor-targeted exosomes and short palindromic repeats interference (CRIS...