Lactylation-mediated remodeling of spatial immunometabolic niches in lung cancer: metabolic origins, cellular interactions, and molecular mechanisms

Hypoxia, abnormal perfusion, and oncogenic signaling increase lactate production in lung cancer and create intercellular fluxes mediated by monocarboxylate transporters. Circulating lactate can be taken up by lung tumors and enter the tricarboxylic acid (TCA) cycle. Lactate therefore acts as a carbon source, a regulator of redox and acid-base homeostasis, and a precursor for lysine L-lactylation. Representative validated modifications include histone H3 lysine 18 lactylation (H3K18la) and histone H4 lysine 5 lactylation (H4K5la) together with nonhistone substrates such as programmed death ligand 1 (PD-L1), hexokinase 2 (HK2), mitochondrial cristae-organizing protein Mic60, and replication protein A1 (RPA1), linking lactylation to transcriptional regulation, protein stability, metabolic adaptation, immune evasion, DNA repair, and treatment resistance in lung cancer. Tumor-derived lactate also reprograms cluster of differentiation 8-positive (CD8 + ) T cells, regulatory T cells, macrophages, dendritic cells, and cancer-associated fibroblasts across hypoxic cores, invasive fronts, perivascular regions, and tertiary lymphoid structure-associated areas. This review integrates lactate-pool formation, lactylation writers and erasers, intracellular reprogramming, immune-stromal interactions, and spatial niches. It distinguishes metabolic and acidification effects of lactate from covalent lactylation and separates direct causal evidence in lung cancer from spatial associations and cross-cancer mechanistic support. This framework defines a source-to-site chain for studying regional lactate activity and lactylation-dependent phenotypes in lung cancer.