Tumor-associated macrophages in gastric cancer peritoneal metastasis: orchestrating immune evasion, niche remodeling, and therapeutic resistance

Vollständiger Abstract

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Peritoneal metastasis is the most devastating form of progression of gastric cancer, characterized by strong immune suppressive properties and resistance to treatment. Tumor-associated macrophages (TAMs) are the main population of immune cells in the peritoneal cavity and participate in nearly every step of this process. In this Review, we focus on the two major origins of peritoneal macrophages (embryonic-derived GATA6+ resident cells and monocyte-derived CCR2+ cells), and we describe how gastric cancer cells exploit their plasticity by metabolic signals, exosomal oncomiRs, paracrine factors and so on to push them into a pro-metastatic phenotype. Reprogrammed macrophages proceed to participate in detachment of tumor cells, resistance to anoikis, escaping across mesothelium and stimulating angiogenesis and lymphangiogenesis, but also instigate an immunosuppressive environment suppressing T cell activity and increasing chemoresistance. Important molecular players that we describe here are CCL2/CCR2 and CSF-1/CSF-1R signaling axes, the STAT3/STAT6/PI3K axis and a complement-driven switch of TAMs from a cathepsin (CTS)-high to complement component 1q(C1q)-high state that promotes immune evasion. We also discuss the role of exosome-mediated cross-talk and give an overview of novel therapies against macrophages such as blocking their recruitment, reprogramming their polarization or using chimeric antigen receptor macrophage (CAR-M) therapy, typically in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) or immune checkpoint inhibitors. Bringing together the latest advances, we highlight key gaps in our understanding and suggest a direction for dismantling the macrophage-orchestrated metastatic niche with the ultimate goal of improving outcomes of this devastating disease.