Histone lactylation increases CXCL1 expression for neutrophil infiltration and immune escape in pancreatic cancer
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons sanguins et d'échantillons tissulaires issus de patients atteints d'un cancer du pancréas ou de témoins en bonne santé, cette étude met en évidence un mécanisme par lequel la lactylation de l'histone H3 favorise l'infiltration des neutrophiles dans la tumeur et l'échappement immunitaire en augmentant l'expression de la chimiokine CXCL1
Aerobic glycolysis and lactate have been shown to modulate tumor microenvironment (TME) and disease progression. Lactate-mediated histone lysine lactylation (Kla) is a newly recognized epigenetic modification whose biological function remains poorly understood. Here, through integrated bioinformatic and experimental analyses, we demonstrate that glycolysis-derived lactate induces histone H3 lysine 18 lactylation (H3K18la) and up-regulates the expression of chemokine C-X-C motif Ligand 1 (CXCL1), thereby recruiting neutrophils and inducing immunosuppression in pancreatic cancer. Moreover, our data suggest that p300/CBP-associated factor (PCAF) functions as a histone lactyltransferase that transcriptionally activates CXCL1 expression. Finally, we reveal that combinational treatment with bromosporine (a PCAF inhibitor) and anti-PD-1 antibody exhibits a synergistic antitumor effect on both subcutaneous and orthotopic tumor models of pancreatic cancer. Taken together, our study not only identifies a mechanism by which the aerobic glycolysis-induced Lactate-PCAF-H3K18la-CXCL1 pathway mediates neutrophil infiltration and immunosuppression, but also develops a potential therapeutic strategy for pancreatic cancer.
Nature Communications , article en libre accès, 2026