Evolving landscape of the gastric cancer immune microenvironment: From spatial architecture to precision biomarkers

Table 2 High-resolution interactome of the gastric cancer microenvironment

Interaction category	Signaling axis (ligand-receptor)	Key cellular sources	Spatial phenotype context	Functional consequence in gastric cancer
Microbial-immune	Fibroblast activation protein 2-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains	Fusobacterium nucleatum to natural killer/T cells	Inflamed/excluded	Direct inhibition of lymphocyte cytotoxicity; “microbial checkpoint“
Neuro-immune	Norepinephrine-β2-AR	Sympathetic nerves to CD8+ T cells	Global (stress-induced)	Inhibition of granzyme B/interferon-γ production via cyclic adenosine monophosphate-protein kinase A signaling
Neuro-myeloid	Acetylcholine-alpha-7 nicotinic acetylcholine receptor	Vagus nerve to TAMs	Excluded/desert	Promotion of M2-like polarization; cholinergic anti-inflammatory shield
Fibro-immune	CXCL12-CXCR4	The myCAFs to T cells	Immune-excluded	Peritumoral T-cell sequestration; prevention of nest infiltration
Fibro-immune	SPP1-CD44	TAMs to myCAFs	Excluded	Strengthening of the extracellular matrix “fortress“ and collagen cross-linking
Vascular-immune	VEGF-A-VEGFR2	Tumor cells to Endothelium	Desert/excluded	Downregulation of intercellular adhesion molecule 1/vascular cell adhesion molecule 1; induction of endothelial anergy
Immune-immune	CXCL13-CXCR5	T follicular helper cells to B cells	Immune-inflamed	Recruitment of B cells to tertiary lymphoid structure; orchestration of germinal center reactions

CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; myCAFs: Myofibroblastic cancer-associated fibroblasts; TAMs: Tumor-associated macrophages; VEGF-A: Vascular endothelial growth factor A; VEGFR2: Vascular endothelial growth factor receptor 2.