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

Table 1 Comparative spatial and molecular metrics of gastric cancer tumor immune microenvironment phenotypes

Metric	Immune-inflamed (“hot“)	Immune-excluded (“cold“)	Immune-desert (“cold“)
Predominant subtype	Epstein-Barr virus+, microsatellite instability-high	Genomically stable (genomically stable)	Chromosomal Instability
Dominant chemokine axis	CXCL9/10/11-CXCR3	CXCL12-CXCR4	Low/absent
B-cell/TLS organization	Mature TLS (secondary follicles) with gastric cancer reaction; high B-cell diversity	Immature TLS or disorganized B-cell aggregates at the margin	Absent or rare B-cell clusters; lack of TLS formation
Stroma density (collagen)	Low/moderate	High (cross-linked lysyl oxidase-like 2 + fibers)	Variable
T-cell factor 1 + T-cell niche	Present in mature TLS	Restricted to invasive margin 15	Absent
Response to anti-programmed cell death protein 1	High (50%-70%)	Low (primary resistance)	Negligible

CXCL: C-X-C motif chemokine ligand; CXCR: C-X-C motif chemokine receptor; TLS: Tertiary lymphoid structure.

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.

Table 3 Integrative landscape of molecular subtypes and immune phenotypes

Molecular subtype	Spatial phenotype	Key genomic drivers	Dominant immune mechanism	Recommended strategy
Epstein-Barr virus+	Inflamed (hot)	9p24.1 amp, PIK3CA mut	Viral pathogen-associated molecular patterns; constitutive programmed death-ligand 1	Programmed cell death protein 1 monotherapy
Microsatellite instability	Inflamed (hot)	Deficient mismatch repair, high tumor mutational burden	Neoantigen-driven recruitment	Dual checkpoint blockade
Genomically stable	Excluded (cold)	CDH1/RHOA mut, CLDN18.2	TGF-β fibrosis; myofibroblastic cancer-associated fibroblasts barriers	Anti-CLDN18.2/TGF-β inhibitors
Chromosomal instability	Desert/variable	TP53 mut, receptor tyrosine kinase amp, somatic copy number alterations	Human leukocyte antigen loss of heterozygosity; myeloid-driven suppression	Targeted + immune checkpoint inhibitors (e.g., human epidermal growth factor receptor 2-directed)

TGF-β: Transforming growth factor beta.

Table 4 Integrative metabolic checkpoints and their epigenetic consequences in gastric cancer

Metabolic axis	Key mediators/enzymes	Effect on the tumor immune microenvironment	Epigenetic and signaling impact	Potential intervention
Glucose/Lactate	Glucose transporter 1, MCT4, LDHA	Local acidification (pH 6.0-6.5); glucose starvation	Histone lactylation (histone H3 lysine 18 lactylation); inhibition of nuclear factor of activated T cells translocation	MCT4 inhibitors; LDH inhibitors
Tryptophan	IDO1, tryptophan 2,3-dioxygenase	Tryptophan depletion; kynurenine accumulation	Activation of Aryl hydrocarbon receptor; Induction of suppressive regulatory T cells via general control nonderepressible 2	IDO1 inhibitors (e.g., Epacadostat)
Arginine	Arg-1	L-arginine starvation	Downregulation of the CD3 zeta-chain; T-cell anergy	Arg-1 inhibitors
Adenosine	CD39, CD73	Adenosine triphosphate to adenosine conversion	Activation of A2aR; intracellular cyclic adenosine monophosphate/protein kinase A signaling	A2aR antagonists (e.g., Ciforadenant)
Lipid/iron	Glutathione peroxidase 4, solute carrier family 7 member 11	Ferroptosis-resistance	Prevention of danger-associated molecular patterns release (suppression of immunogenic cell death)	Ferroptosis inducers (e.g., RAS-selective lethal 3)
Epigenetic/viral	DNA methyltransferase 1, EZH2	Silencing of endogenous retroviruses and human leukocyte antigen genes	Major histocompatibility complex class I transcriptional silencing; viral mimicry failure	DNA methyltransferase inhibitors; EZH2 inhibitors

Arg-1: Arginase-1; A2aR: A2a receptor; EZH2: Enhancer of zeste homolog 2; IDO1: Indoleamine 2,3-dioxygenase 1; LDH: Lactate dehydrogenase; MCT4 Monocarboxylate transporter 4.

Table 5 Mechanism-guided ecosystem engineering strategies in gastric cancer

Engineering objective	Target mechanism/axis	Therapeutic strategy	Biological rationale	Representative agents/trials
Breaching physical barriers	Myofibroblastic cancer-associated fibroblasts-lysyl oxidase-like 2/TGF-β	TGF-β traps; Fibroblast activation protein-targeted chimeric antigen receptor T cells	Dismantling the collagen “fortress“ to enable T-cell infiltration	Vactosertib; AB122
Normalizing the niche	VEGF-A/VEGFR2	Anti-angiogenesis + immune checkpoint inhibitor	Reversing endothelial anergy; reducing high interstitial fluid pressure	Regorafenib + Nivolumab (LEAP-005)
Metabolic rescue	Lactate/histone H3 lysine 18 lactylation	Monocarboxylate transporter 4 or lactate dehydrogenase inhibitors	Reversing histone lactylation to “unlock“ suppressive TAMs	Preclinical/early phase
Metabolic rescue	Adenosine/A2aR	CD73 inhibitors; A2aR antagonists	Abrogating cyclic adenosine monophosphate -mediated paralysis in the hypoxic core	Oleclumab; Ciforadenant
Priming immunity	ADC-induced immunogenic cell death	Trastuzumab deruxtecan; CLDN18.2-ADC	Triggering danger-associated molecular patterns release (calreticulin/high-mobility group box-1) to activate conventional type 1 dendritic cells	DESTINY-gastric03
Dual checkpoint synergy	Programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4	Bispecific antibodies	Simultaneous modulation of priming (lymph node) and effector (tumor) phases	Cadonilimab (AK104)
Neural modulation	Β2-AR signaling	Repurposed β-blockers	Preventing stress-induced catecholamine inhibition of cytotoxic T lymphocytes fitness	Propranolol (phase II)

ADC: Antibody-drug conjugate; A2aR: A2a receptor; TGF-β: Transforming growth factor beta; VEGF-A: Vascular endothelial growth factor A; VEGFR2: Vascular endothelial growth factor receptor 2.