Metastasis is the leading cause of death in triple-negative breast cancer (TNBC), yet how tumor cells evade immune recognition during dissemination remain unclear. Here, we show that de novo lipogenesis drives metastatic immune evasion through FASN-mediated palmitoylation of EGFR. This modification establishes a lipid-dependent membrane signaling scaffold that sustains PI3K-AKT-mTOR signaling independently of MAPK compensation, thereby suppressing MHC-I antigen presentation through post-translational regulation. As a result, metastatic-competent cells escape CD8+ T cell surveillance and colonize distant organs. Genetic or pharmacologic inhibition of fatty acid synthase (FASN), or expression of palmitoylation-deficient EGFR mutants restores MHC-I surface expression, unleashes robust CD8 T cell activation, and markedly impairs lung metastasis without affecting primary tumor growth. This lipid-dependent EGFR-PI3K-mTOR axis operates independently of MAPK signaling and is not rescued by exogenous lipids, revealing a non-redundant metabolic dependency. Our results identify FASN-driven EGFR palmitoylation as a tumor-intrinsic immunometabolic checkpoint that couples lipid metabolism to antigen-presentation and metastatic competence. Targeting this pathway with clinically advancing FASN inhibitors offers a promising strategy to suppress metastasis by restoring anti-tumor immunity in TNBC.
Ko, M. S., Ramchandani, D., Simmons, G., McCormick, J., Carrasco, S., Singh, A., Yoffe, L., Zhang, G., Mittal, V.
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