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The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.

The oncogenic expression or mutation of tumor suppressors drives metabolic alteration, causing cancer cells to utilize diverse nutrients. Lactate is a known substrate for cancer cells, yet the regulatory mechanisms of lactate catabolism are limited. Here, we show that a heme-binding transcription factor, BACH1, negatively regulates lactate catabolic pathways in triple-negative breast cancer (TNBC) cells. BACH1 suppresses the transcriptional expression of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase B, inhibiting lactate-mediated mitochondrial metabolism. In our studies, the depletion of BACH1 either genetically or pharmacologically increased the lactate use of TNBC cells, increasing their sensitivity to MCT1 inhibition. Thus, small inhibitory molecules (SR13800 and AZD3965) blocking MCT1 better suppressed the growth of BACH1-depleted TNBC cells than did the controls. Particularly, hemin treatment degrading BACH1 proteins induced lactate catabolism in TNBC cells, generating synthetic lethality with MCT1 inhibition. Our data indicates that targeting BACH1 generates metabolic vulnerability and increases sensitivity to lactate transporter inhibition, suggesting a potential novel combination therapy for cancer patients with TNBC.

The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe 3+ , which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe 3+ to Fe 2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe 2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe 3+ , which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.