Exosomal Biglycan promotes gastric cancer progression via M2 polarization and CXCL10-mediated JAK/STAT1 activation

Abstract

Recent advancements in tumor immunotherapy have highlighted the importance of the tumor microenvironment in modulating immune responses against cancer cells. Within the TME, macrophages - particularly the M2 phenotype - serve pivotal regulatory functions through cytokine/chemokine secretion to modulate tumor progression. Elucidating the molecular crosstalk between gastric cancer (GC) cells and tumor-associated macrophages (TAMs) remains imperative for developing targeted therapeutic interventions. In this study, we identified Biglycan (BGN), a small leucine-rich proteoglycan, as a key mediator in GC progression. Exosomal BGN derived from GC cell is delivered to macrophages, where it binds to NONO protein, thereby driving M2 polarization and upregulating CXCL10 expression. Elevated CXCL10 levels activate the JAK/STAT1 signaling pathways, thereby potentiating GC cell proliferation, invasion, and metastatic dissemination. Clinically, elevated BGN expression correlates with advanced tumor stage and poor prognosis in GC patients, positioning it as a promising therapeutic target. Our findings reveal a previously unrecognized mechanism of exosomal BGN-mediated M2 macrophage reprogramming and CXCL10-driven oncogenic signaling in the GC microenvironment. These insights establish a novel therapeutic paradigm for GC management through disruption of tumor-macrophage communication.

Keywords: Chemokine axis; JAK/STAT activation; Proteoglycan signaling; Stromal remodeling; Tumor-associated macrophages.