Ketogenic diet impairs NK cell cytotoxic function in colorectal cancer liver metastasis by inducing ferroptosis via suppression of the p62-Keap1-Nrf2 pathway

Emerging evidence suggests the ketogenic diet (KD) may modulate cancer progression, though its impact on colorectal cancer liver metastasis (CRLM) remains poorly characterized. Our study demonstrates that a KD promotes CRLM in a mouse model. Untargeted metabolomics identifies specific phosphatidylethanolamine (PE) metabolites as key mediators of this effect. Using single-cell RNA sequencing (scRNA-seq) and flow cytometry, we find that enhanced metastasis critically depends on KD-induced impairment of NK cell cytotoxicity and viability. This aligns with reduced NK cell numbers within the tumor microenvironment (TME) of CRLM patients compared to non-metastatic CRC patients, as shown by immunofluorescence staining. Further analysis reveals that PE compromises NK cell anti-tumor function both in vivo and in vitro by suppressing key effector cytokines, including IFN-γ, TNF-α, and Granzyme B. Mechanistically, PE treatment reduces p62 and Nrf2 levels in TME-resident NK cells, attenuating cellular antioxidant defenses and ultimately inducing ferroptosis-characterized by iron overload, elevated lipid ROS, and mitochondrial fragmentation. Reduced p62 and Nrf2 expression in TME NK cells of CRLM patients (vs. non-metastatic CRC patients) suggests their potential as future biomarkers. Functionally targeting Nrf2 with TBHQ significantly alleviates PE-induced NK cell ferroptosis and boosts NK cell cytotoxicity against CRLM. This study provides new insights into how dietary metabolites reshape antitumor immunity and suggests potential therapeutic strategies to enhance NK cell-based immunotherapies for CRLM.