AKR1B10 reprograms neutrophils by histone lactylation to foster immune evasion in KRASG12C mutation colorectal cancer liver metastasis

Abstract Background The KRASG12C mutation is one of the special mutation types in patients with colorectal cancer liver metastasis (CRLM). Although several small molecule inhibitors specifically targeting KRASG12C mutation have been developed, they have only shown limited clinical benefits for CRLM patients. Thus, alternative approaches are still needed. Methods We screened out the differentially expressed gene Aldo–keto reductase family 1 member B10 (AKR1B10) between the KRASG12C mutation and wild-type CRLM through RNA sequencing, and characterized the tumor microenvironment (TME) changes of the KRASG12C mutation CRLM using multi-omics analysis. The role of AKR1B10 in the TME and its progression of KRASG12C mutation CRLM was confirmed by in vitro and in vivo experiments, and the molecular mechanism of lactate on neutrophils reprogramming was detected by immunofluorescence, western blot and Chip-qPCR. Results AKR1B10 was highly expressed in the KRASG12C mutation CRLM and was associated with a poor prognosis. Mechanistically, AKR1B10 promotes the recruitment of neutrophils in the TME by CXCL8/CXCR2 pathway. Meanwhile, AKR1B10 could promote the production of lactate by regulating crucial glycolytic enzymes. The increased lactate accumulation in the TME promoted histone lactylation of neutrophils, which induced PD-L1 transcription and prompted the reprogramming of neutrophils to an immunosuppressive phenotype. Conclusion AKR1B10 facilitated immune evasion of KRASG12C mutation CRLM by recruiting and reprogramming neutrophils to remodel the immunosuppressive TME, providing a potential therapeutic target for KRASG12C mutation CRLM patients. Graphical Abstract