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![Lactate-mediated metabolic crosstalk
in the lung tumor microenvironment. Tumor-derived lactate is
transported through MCT1/4 and promotes extracellular
acidification, CAF-tumor metabolic exchange, angiogenesis,
immune-cell dysfunction and immunosuppressive cell activity.
Histone and non-histone lactylation further contribute to
transcriptional reprogramming and immune suppression. CAF,
cancer-associated fibroblast; MCT, monocarboxylate transporter;
MHC, major histocompatibility complex; DC, dendritic cell; SGK1,
serum/glucocorticoid-regulated kinase 1; MDSC, myeloid-derived
suppressor cell; Arg1, arginase 1; TAM, tumor-associated
macrophage; IFN, interferon; H3K18la, histone H3 lysine 18
lactylation; H4K12la, histone H4 lysine 12 lactylation; LDHA,
lactate dehydrogenase A; RPA1, replication protein A1; APOC2,
apolipoprotein C-II; NFAT, nuclear factor of activated T-cells;
GLUT1, glucose transporter 1; bFGF, basic fibroblast growth factor;
EC, endothelial cell; Treg, regulatory T-cell; FOXP3, forkhead box
P3. The figure was created in BioRender [Zhang Y (2026) https://BioRender.com/b8eadbd].](/article_images/or/56/4/or-56-04-09187-g00.jpg)
![Lactate-mediated pan-therapeutic
resistance in lung cancer. The LDHA-lactate-MCT1/4 axis forms a
central resistance hub connecting metabolic support, prosurvival
signaling, lactylation, immune escape and redox regulation, thereby
promoting resistance to chemotherapy, targeted therapy,
immunotherapy and radiotherapy. LDHA, lactate dehydrogenase A; MCT,
monocarboxylate transporter; PD-1, programmed cell death protein 1;
PD-L1, programmed death-ligand 1; YTHDF2, YTH
N6-methyladenosine RNA-binding protein 2;
m6A, N6-methyladenosine; AMBRA1, autophagy
and beclin 1 regulator 1; POM121, POM121 transmembrane nucleoporin;
H3K18la, histone H3 lysine 18 lactylation; H4K12la, histone H4
lysine 12 lactylation; ROS, reactive oxygen species; ATP, adenosine
triphosphate; mTOR, mechanistic target of rapamycin; MET, MET
receptor tyrosine kinase; HGF, hepatocyte growth factor; GPR81, G
protein-coupled receptor 81. The figure was created in BioRender
[Zhang Y (2026) https://BioRender.com/f5p2epm].](/article_images/or/56/4/or-56-04-09187-g01.jpg)
