Lipid metabolism and the immune microenvironment in gastric cancer.

The treatment of gastric cancer (GC) has entered an era of precision medicine combining molecular subtyping, immune checkpoint inhibitors (ICIs), anti-human epidermal growth factor receptor 2 (HER2), anti-claudin 18.2 (CLDN18.2), anti-angiogenic therapy, and chemotherapy. However, efficacy remains limited by tumor microenvironment (TME) heterogeneity, immune exclusion, myeloid suppression, nutrient competition, and metabolic adaptation. Lipid metabolic reprogramming represents a class of mechanisms with high translational value among metabolic immune checkpoints in GC: it supports tumor-cell membrane synthesis, redox homeostasis, peritoneal/omental metastasis, and adaptation to therapeutic stress, while also affecting regulatory T cells (Tregs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells, and CD8+ T cells. This review focuses on cluster of differentiation 36 (CD36)-mediated fatty acid uptake; carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO); fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), sterol regulatory element-binding protein 1 (SREBP-1), and stearoyl-CoA desaturase 1 (SCD1)-mediated de novo lipogenesis; cholesterol and lipid-droplet metabolism; lipid-mediated post-translational modifications; lipid peroxidation; and ferroptosis. Lipid metabolism-targeted therapy should be positioned as a biomarker-driven combination strategy rather than as non-selective monotherapy. Future studies should integrate single-cell and spatial transcriptomics with lipidomics, imaging mass spectrometry, and paired pre- and post-treatment biopsies to define cell type-specific lipid dependencies and pharmacodynamic markers. Clinical translation will require prospective validation that a candidate intervention changes the intended lipid pathway in the intended tumor or immune-cell compartment without disabling metabolically essential normal tissues.