Advances in molecular mechanism of gastric cancer peritoneal metastasis

Table 4 Tumor microenvironment components in gastric cancer peritoneal metastasis: Functions, interactions, and therapeutic opportunities

TME component	Subset/key factor	Mechanisms	Key interactions	Potential therapeutic targets
CAFs	General CAFs	Immunosuppression; tumor survival/stemness; angiogenesis; invasion	Interact with tumor cells, immune cells, and endothelial cells	FAP inhibitors; IL-6R antibody
	apCAFs (CD74+, HLA-DRA+)	Antigen-presenting function	Spatially enriched around tertiary lymphoid structures	Prognostic biomarker; predict immunotherapy response
	myCAFs (GDF15-driven)	Form dense physical barrier; impede CD8+ T cell infiltration	Interact with tumor cells	Target GDF15 to relieve immune exclusion
TAMs	M2-like TAMs	Immunosuppression; angiogenesis; ECM remodeling	Interact with tumor cells, immune cells, CAFs and endothelial cells	TAM reprogramming (anti-DKK1, anti-IL10, anti-POU1F1)
	CTSL+ TAMs	Establish pre-metastatic microenvironment; mediate tumor cell “homing”	Dynamic lineage transition to C1Q+ TAMs	Target CTSL
	C1Q+ TAMs	Drive proliferation, immune evasion, therapeutic resistance	Dynamic lineage transition from C1Q+TAMs	C1 inhibitor
	SPP1+ TAMs	Immunosuppression	Interact with THBS2+ CAFs	C3aR antagonists
	VCAN+ TAM	Angiogenesis, immunosuppression and chemotherapy resistance	-	Target VCAN
Adipocytes	-	Secrete CXCL2 → AKT-HIF1α-VEGFA axis (angiogenesis); LAMC1 drives preadipocyte differentiation → releases free fatty acids (metabolic reprogramming); NSUN2/ORAI2 activates PI3K-AKT (proliferation/migration)	Interact with tumor cells	Omentectomy; serum LAMC1 as biomarker; urinary CXCL2 as biomarker; FAO inhibitors
Angiogenesis	VEGF/VEGFR; ESM1/c-Met; CAF-derived HGF	VEGF/VEGFR primary pathway; ESM1 activates MAPK → HIF-1α/VEGFA/MMP-9; CAF-derived HGF promotes multiple vascular patterns	-	Anti-VEGF/VEGFR (bevacizumab, ramucirumab); ESM1 antibody; c-Met inhibitors; HGF inhibitors PI3K/MEK/ERK inhibitors

This table summarizes the key components of the tumor microenvironment in gastric cancer peritoneal metastasis, including cancer-associated fibroblasts, tumor-associated macrophages, angiogenic factors, and adipocytes. It highlights their pro-tumor mechanisms, intercellular interactions, and potential therapeutic targets for clinical translation. TME: Tumor microenvironment; CAFs: Cancer-associated fibroblasts; TAMs: Tumor-associated macrophages; FAP: Fibronectin attachment protein; IL-6R: Interleukin-6 receptor; apCAFs: Antigen-presenting cancer-associated fibroblasts; GDF-15: Growth differentiation factor 15; DKK1: Dickkopf-1; IL10: Interleukin-10; POU1F1: POU class 1 homeobox1; CTSL: Cathepsin L; SPP1: Secreted phosphoprotein 1; THBS2: Thrombospondin 2; VCAN: Versican; CXCL2: C-X-C motif chemokine ligand 2; FAO: Fatty acid oxidation; AKT: Protein kinase B; HIF1α: Hypoxia-inducible factor 1alpha; VEGFA: Vascular endothelial growth factor A; LAMC1: Laminin gamma 1; NSUN1: NOL1/NOP2/sun family; PI3K: Phosphatidylinositide 3-kinase; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; ESM1: Endothelial cell-specific molecule 1; HGF: Hepatocyte growth factor; MAPK: Mitogen-activated protein kinase; MMP-9: Matrix metallopeptidase 9.