Kupffer cell M2-like polarization increases liver metastatic burden via uptake of exosomal KRAS mutant protein from hypoxic colorectal carcinoma cells

Abstract

Backgrounds: This study is to investigate the metastasis promoting effect of colorectal carcinoma cells-derived exosomes in liver metastasis, M2-like polarization of Kupffer cells and the mechanism underlying. Methods: Mouse liver metastasis models were established to testify the involvement of CRC-derived exosomes on liver metastasis, DIR and PKH26 fluorescent labeling strategy were utilized to trace the distribution of CRC-derived exosomes in vivo. GO and KEGG analysis of differential expressed genes revealed the key cellular regulator and KRAS-induced signaling in CRC liver metastasis. Phenotype of Kupffer cells were determined by IHC and IF. Vitro model HMDMs were used to explore polarization phenotype and therapeutic effects of GSK690693 (AKT inhibitor) inhibited AKT. Results: Exosomal mutant KRAS induced AKT signaling in the process of Kupffer cells M2-like polarization, promoting the CRC liver metastasis. AKT inhibitors might potentially be used as a therapeutic approach to prevent liver metastases in CRC. Conclusion: Our findings reveal that exosomal mutant KRAS drives Kupffer cell M2-like polarization via hyperactivation of AKT signaling, establishing this axis as a key mediator of colorectal cancer liver metastasis. Pharmacological inhibition of AKT effectively disrupts this immunosuppressive reprogramming, proposing targeted AKT blockade as a promising strategy to intercept the metastatic niche in CRC patients.