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Autophagy plays a crucial role in tumor initiation and progression. However, targeting autophagy in cancer has proven challenging due to genetic or epigenetic factors that may affect the efficacy of autophagy inhibition. Therefore, identifying biomarkers is crucial for selecting patients who are likely to benefit from this treatment modality. We show that dysregulation of mitochondrial translation caused by CBFB (core-binding factor subunit beta) deficiency can sensitize the tumors to autophagy inhibition. CBFB and its binding partner HNRNPK (heterogeneous nuclear ribonucleoprotein K) interact with mRNAs encoded by the mitochondrial genome (mt-mRNAs) and maintain their translation. Specifically, CBFB enhances the binding of TUFM (Tu translation elongation factor, mitochondrial), an elongation factor for mitochondrial translation, to mt-mRNAs. CBFB deficiency, which often occurs in estrogen receptor-positive breast tumors, results in elevated autophagy and mitophagy that promote cancer cell survival. Consequently, these cells are hypersensitive to autophagy inhibition, creating a targetable vulnerability. Studies using  in vivo  models have shown that inhibiting autophagy selectively eliminates breast tumor cells with mitochondrial translation defects resulting from CBFB deficiency. Our results suggest that autophagy inhibition may be an effective treatment option for breast tumors carrying CBFB alterations. AMPK, AMP-activated protein kinase; BioID, biotinylation identification; CBFB, core-binding factor subunit beta; HCQ, hydroxychloroquine; HNRNPK, heterogeneous nuclear ribonucleoprotein K; PDX, patient-derived xenograft; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; TUFM, Tu translation elongation factor, mitochondrial; ETC, electron transport chain

Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency