Exosome-Mediated Macrophage Polarization in Gastric Cancer: Inflammatory and Neuroinflammatory Mechanisms and...

Gastric cancer progression is driven by intricate crosstalk among exosomes, macrophage polarization, inflammatory dysregulation, and tumor-associated neuroinflammation within the tumor microenvironment, which collectively form a reciprocal vicious cycle. As critical intercellular mediators, exosomes derived from tumor cells, immune cells, and stem cells deliver microRNA cargos to orchestrate M1/M2 macrophage balance and modulate neuroinflammatory states, exerting either pro-tumor or anti-tumor effects. M1 macrophage-derived exosomal miRNAs suppress PD-L1 and NLRP3 signaling, reduce pro-inflammatory cytokine release, ameliorate neuroinflammation, and enhance anti-tumor immunity. Conversely, tumor cell- and M2 macrophage-derived exosomes drive M2 polarization via the MAPK/ERK and PI3K/Akt pathways, amplifying the secretion of immunosuppressive cytokines and exacerbating neuroinflammatory progression. Stem cell- and traditional Chinese medicine-derived exosomes reverse immunosuppression by targeting the STAT3 pathway, polarize macrophages toward the M1 phenotype, and attenuate tumor-associated neuroinflammation. These regulatory events converge on the NF-κB and NLRP3 inflammasome pathways to shape the inflammatory and neuroinflammatory microenvironment. Preclinical evidence confirms that exosome-based interventions reduce tumor burden by remodeling macrophage phenotypes, restoring inflammatory homeostasis, and ameliorating neuroinflammation. This review identifies exosomal regulators as promising targets for rebalancing macrophage polarization, inflammation, and neuroinflammation, providing a framework for advancing gastric cancer therapeutics.