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

Yilin Li1, Jiaqi You2, Zifang Zou1

  • 1Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang 110002, China.

International Journal of Biological Sciences
|July 4, 2025
PubMed

Insights

Tumor-derived exosomes, regulated by HIF-1α under hypoxia and ERS, modulate macrophage polarization and immune evasion. Engineering exosomes offers potential for cancer immunotherapy by targeting tumor microenvironment interactions.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • The tumor microenvironment (TME) involves complex interactions, with tumor-associated macrophages (TAMs) playing critical roles in cancer progression.
  • Exosomes mediate intercellular communication and are vital in regulating macrophage polarization within the TME.
  • Hypoxia and endoplasmic reticulum stress (ERS) significantly influence tumor cell behavior and exosome production.

Purpose of the Study:

  • To systematically review the role of Hypoxia-inducible factor 1-alpha (HIF-1α) in regulating tumor-derived exosomes under hypoxic conditions.
  • To elucidate the molecular pathways (STAT3, PI3K/AKT/mTOR, Hsp90/Hippo) involved in exosome biogenesis and secretion under ERS.
  • To evaluate the involvement of TAM-derived exosomes in immune evasion, metastasis, and their interactions with other TME components, and discuss exosome engineering strategies for immunotherapy.

Main Methods:

  • Systematic review of existing literature on tumor-derived exosomes, HIF-1α, macrophage polarization, and related signaling pathways.
  • Analysis of molecular mechanisms including LncRNA HMMR-AS1, specific miRNAs (miR-1246, let-7a, miR-301a-3p, miR-23a-3p, miR-27a-3p), and PD-L1 expression.
  • Evaluation of exosome interactions with immune cells (CD8+ T cells) and stromal components (fibroblasts) within the TME.

Main Results:

  • HIF-1α is identified as a central regulator of tumor-derived exosomes under hypoxia.
  • ERS activates STAT3 and PI3K/AKT/mTOR pathways via Hsp90/Hippo inactivation, inducing specific lncRNAs and miRNAs that influence exosome content.
  • Exosomes carry miRNAs and PD-L1, promoting M2 macrophage polarization, immune evasion, and metastasis; bidirectional crosstalk with TME components is confirmed.

Conclusions:

  • Tumor-derived exosomes, particularly those influenced by hypoxia and ERS, are key players in shaping the TME and promoting cancer progression.
  • Understanding the molecular regulation of exosome secretion and content is crucial for developing targeted cancer therapies.
  • Exosome engineering strategies, combined with advanced omics and AI, hold promise for translating exosomes into effective clinical immunotherapy regimens, though challenges remain.

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