Galectin-9-driven immunosuppressive macrophage population shapes the lymph node metastatic microenvironment

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Lymph node (LN) metastasis is a key prognostic indicator and driver of systemic immune suppression.
• Mechanisms of immune escape within LNs are not well understood.

Purpose of the Study:

• To investigate the mechanisms of immune suppression within metastatic lymph nodes.
• To identify dominant immunosuppressive cell populations and their molecular features in LNs.

Main Methods:

• Pan-cancer single-cell transcriptomic analysis of 132 samples across 11 cancer types.
• Unsupervised clustering and cell-type annotation to identify immunosuppressive populations.
• In vitro and in vivo functional assays to elucidate signaling pathways.

Main Results:

• Metastatic LNs show a more immunosuppressive microenvironment than primary tumors.
• Enrichment of IL-10-producing Galectin-9high macrophages in LNs.
• Galectin-9 activates BTK/STAT3 pathway, promoting IL-10 secretion and immune tolerance.

Conclusions:

• A Galectin-9/BTK/STAT3 axis drives macrophage-mediated immune suppression in LN metastases.
• STAT3 inhibition and PD-1 blockade reduced LN metastatic burden.
• This axis presents a potential therapeutic target for overcoming cancer immune escape.