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

[BACKGROUND] The KRAS mutation is one of the special mutation types in patients with colorectal cancer liver metastasis (CRLM). Although several small molecule inhibitors specifically targeting KRAS 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 KRAS mutation and wild-type CRLM through RNA sequencing, and characterized the tumor microenvironment (TME) changes of the KRAS mutation CRLM using multi-omics analysis. The role of AKR1B10 in the TME and its progression of KRAS 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 KRAS 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 KRAS mutation CRLM by recruiting and reprogramming neutrophils to remodel the immunosuppressive TME, providing a potential therapeutic target for KRAS mutation CRLM patients.