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

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.