I. Introduction: The Anti-Cancer Potential of Metformin, a Miracle Drug for Glycemic Control
First synthesized in 1922 and clinically approved in 1957, metformin remains the world's most widely prescribed therapeutic agent for type 2 diabetes to this day. Continuous advances in basic research have yielded substantial evidence that metformin exerts activity inhibiting tumor cell proliferation, endowing it with broad prospects for anti-tumor research and development. A landmark mouse model study recently published in Nature delivers an innovative strategy for combination therapy with metformin to combat triple-negative breast cancer.
II. New Research in Nature: Heme Combined with Metformin for Targeted Therapy of Triple-Negative Breast Cancer
2.1 Background of Heme and Its Target BACH1
Heme was first crystallized and isolated from blood in 1853, and is currently clinically administered mainly for disorders associated with defective heme biosynthesis. This study is the first to identify BACH1 (BTB and CNC homology 1), a transcription factor, as the anti-tumor target of heme. BACH1 is highly expressed in triple-negative breast cancer (TNBC) and acts as a core protein mediating tumor metastasis; high BACH1 expression generally predicts poor patient prognosis. This transcription factor governs mitochondrial metabolism by binding to specific DNA sequences to suppress transcription of genes related to the mitochondrial electron transport chain, thereby cutting off one major energy supply pathway for tumor cells. Moreover, BACH1 is not an essential target for cell survival, meaning targeted inhibition of this protein may enable low-toxicity therapeutic regimens.
2.2 Mechanism of Combination Therapy and Outcomes of Animal Experiments
In vitro cellular assays demonstrated that heme treatment downregulates BACH1 expression and forces metabolic reprogramming in tumor cells. Building on prior research findings, the research team proposed a hypothesis: tumor cells undergoing altered metabolic pathways become far more susceptible to metformin-mediated suppression of mitochondrial respiration. Subsequent mouse xenograft tumor models validated this hypothesis: the combined regimen of heme plus metformin effectively suppressed the growth of triple-negative breast tumors.
2.3 Guidance for Individualized Medication and Prospect of Broad-Spectrum Anti-Cancer Application
The study put forward a stratified therapeutic framework:
Patients with low BACH1 expression and high expression of mitochondrial-related genes exhibit robust therapeutic responses to metformin monotherapy;
Patients with high BACH1 expression and low expression of mitochondrial-related genes are inherently resistant to metformin. Co-administration with heme reverses drug resistance and restores tumor sensitivity to metformin.
Researchers emphasized that BACH1 overexpression is not exclusive to triple-negative breast cancer; elevated levels of this protein are also detected in multiple malignancies including lung cancer, renal carcinoma, uterine cancer, prostate cancer and acute myeloid leukemia. Hence, this therapeutic strategy holds promise for expansion across various cancer types. This study also marks the world's first investigation into the anti-tumor combinatorial regimen pairing metformin with heme.
III. Research in Nature Communications: Development of Triple Combination Therapy for Breast Cancer Incorporating Metformin
3.1 Target Background: MYC-Mediated Metabolic Vulnerabilities in Tumors
The MYC oncogene is overexpressed in more than 40% of breast cancers, triggering metabolic defects in tumor cells that render cancer cells prone to apoptosis. Leveraging this characteristic, a research team from the University of Helsinki in Finland explored a novel drug combination. Venetoclax, a BCL-2 inhibitor approved by the FDA for certain hematological malignancies, induces tumor cell apoptosis but has not yet obtained regulatory approval for breast cancer indications. Screening experiments revealed that metformin amplifies the pro-apoptotic effect of venetoclax.
3.2 Efficacy and Limitations of Dual-Drug Regimen: Metformin plus Venetoclax
In vitro cell cultures, breast cancer animal models and patient-derived tumor tissue samples all confirmed that the combination of metformin and venetoclax exploits MYC-induced metabolic vulnerabilities to eliminate breast cancer cells and curb tumor progression. Nevertheless, this dual-agent regimen carries prominent limitations. In mouse models, combined treatment only achieves temporary tumor control, with rapid tumor relapse upon drug withdrawal. Mechanistic analysis indicated that dual-drug therapy triggers massive exhaustion of tumor-killing lymphocytes, while residual immune cells display high PD-1 expression, establishing an immunosuppressive tumor microenvironment.
3.3 Triple Combination Therapy: Metformin + Venetoclax + PD-1 Antibody
In response to the reshaped immune microenvironment, the research team incorporated a PD-1 antibody to construct a triple therapeutic regimen:
Metformin combined with venetoclax: reduces tumor lesions, induces cancer cell apoptosis and activates cytotoxic lymphocytes;
PD-1 antibody: relieves immune suppression and sustains the anti-tumor activity of lymphocytes. Animal experiments verified that the triple combination therapy significantly prolongs the survival of tumor-bearing mice compared with monotherapy or dual-drug regimens. All three agents in this regimen are commercially available approved drugs, creating favorable conditions for rapid translation into human clinical trials.
IV. Extended Background: Current Clinical Treatment Landscape of Triple-Negative Breast Cancer
Triple-negative breast cancer (TNBC) accounts for 15% to 20% of all breast cancer cases, with a higher incidence among young women. It is characterized by elevated recurrence risk, propensity for distant metastasis and relatively high mortality rates. At present, most patients can only receive conventional chemotherapy, which frequently induces drug resistance and results in suboptimal overall prognosis. Previously, the New England Journal of Medicine (NEJM) published pivotal clinical progress: the combination of atezolizumab (a PD-L1 antibody) and albumin-bound paclitaxel received FDA approval, becoming the world's first first-line targeted immunotherapy regimen indicated for triple-negative breast cancer.
V. Conclusion
Two high-impact studies established two distinct combination therapeutic approaches for breast cancer centered on metformin: the heme-based regimen targets BACH1 to modulate mitochondrial metabolism, while the triple-agent therapy exploits MYC-driven metabolic vulnerabilities alongside immune checkpoint inhibitors. As a classic decades-old marketed pharmaceutical, metformin boasts well-established safety profiles and controllable treatment costs. It is expected to accelerate the clinical translation of novel therapies for multiple refractory breast cancers, and follow-up data from relevant clinical trials warrants sustained attention.
