CAFs promote immune evasion in gastric cancer through histone lactylation-mediated suppression of NCAPG ubiquitination.

Background: Cancer-associated fibroblasts (CAFs) can facilitate tumor progression through multiple approaches. Research indicates that CAFs in various tumors exhibit robust lactate metabolism, ultimately becoming the primary source of lactate in the tumor microenvironment. Emerging evidence has established that CAFs could orchestrate gastric cancer (GC) immune evasion. However, the potential role of CAFs-derived lactate in immunotherapy remains elusive.

Methods: In our research, CUT&Tag and transcriptome sequencing were employed to detect the target gene of histone lactylation. Co-immunoprecipitation, mass spectrometry analysis, and molecular docking, were utilized to explore the interactions between proteins. We performed cellular, animal, and organoid experiments to verify the mechanism.

Results: We found that lactate secreted by CAFs was elevated, facilitating the lactylation of H3K18 in GC cells. As a target of H3K18la, ASPM played crucial roles in regulating the GC progression by promoting resistance to anti-PD-1. Mechanistically, ASPM promoted the transport of NCAPG from the nucleus to the cytoplasm by directly binding to it and then enhanced the deubiquitination of NCAPG mediated by BUB3, thereby increasing the expression of NCAPG. Furthermore, NCAPG targeted the SRC/STAT3 pathway and elevated PD-L1 expression. In addition, Daturilin has been preliminarily identified as a small-molecule inhibitor targeting NCAPG.

Conclusions: In conclusion, we have identified that CAFs-derived lactate promoted GC progression and clarified its mechanism, proposing the H3K18la-ASPM-NCAPG axis. Daturilin could enhance the therapeutic efficacy of anti-PD-1 treatment. This offers innovative perspectives on the complex role of CAFs in the TME and the influence of lactate on tumor progression.