Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Adipose-tissue macrophages (ATMs) are key components of the tumor-adipose microenvironment (TAME).
• Tumor-adipocyte interactions influence macrophage plasticity and function, but mechanisms remain unclear.
• Identifying these mechanisms is crucial for understanding and targeting cancer progression.

Purpose of the Study:

• To elucidate the mechanisms by which tumor-adipocyte crosstalk regulates macrophage behavior in the TAME.
• To investigate the role of exosomal microRNA-155 (miRNA-155) in mediating this crosstalk.
• To evaluate the therapeutic potential of targeting this pathway in preclinical cancer models.

Main Methods:

• Single-cell RNA-sequencing of macrophages in the TAME.
• Co-culture systems of tumor cells and adipocytes.
• Analysis of exosomal miRNA levels and their downstream effects on adipocyte and macrophage function.
• In vivo studies involving genetic manipulation (macrophage deletion, miRNA inhibition) and pharmacological inhibition (chemokines, STAT3 phosphorylation).

Main Results:

• A subset of immunosuppressive CD163+ macrophages expressing CCL2 and CCL5 were identified in the TAME, surrounding adipocytes.
• Exosomal miRNA-155 levels were elevated in tumor-adipocyte co-cultures, promoting CCL2 and CCL5 release from adipocytes via the SOCS6/STAT3 pathway.
• Inhibition of exosomal miRNA-155 reduced CCL2/CCL5 levels and tumor growth.
• Macrophage deletion, chemokine inhibition, or STAT3 suppression decreased adipocyte-induced tumor proliferation.

Conclusions:

• Exosomal miRNA-155 secreted by tumor cells in the TAME drives adipocyte-mediated immunosuppression and macrophage polarization.
• This miRNA-155/adipocyte/macrophage axis represents a critical mechanism for tumor progression.
• Targeting exosomal miRNA-155 or downstream signaling pathways holds therapeutic promise for cancers associated with the TAME.