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

<i>Background</i>: this study investigates the metastasis-promoting effect of colorectal carcinoma cell-derived exosomes in liver metastasis, M2-like polarization of Kupffer cells, and the underlying mechanism. <i>Methods</i>: mouse liver metastasis models were established to determine the involvement of CRC-derived exosomes in liver metastasis. The DIR and PKH26 fluorescent labeling strategies were utilized to trace the distribution of CRC-derived exosomes <i>in vivo</i>. GO and KEGG analyses of differentially expressed genes revealed the key cellular regulator and KRAS-induced signaling in CRC liver metastasis. The phenotype of Kupffer cells was determined by IHC and IF. <i>In vitro</i> model HMDMs were used to explore polarization phenotype and therapeutic effects of GSK690693 (AKT inhibitor) inhibited AKT. <i>Results</i>: exosomal mutant KRAS induced AKT signaling in the process of Kupffer cell M2-like polarization, promoting CRC liver metastasis. AKT inhibitors might potentially be used as a therapeutic approach to prevent liver metastasis in CRC. <i>Conclusion</i>: our findings reveal that exosomal mutant KRAS drives Kupffer cell M2-like polarization <i>via</i> the 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.