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

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.