Evaluating Therapeutic Efficacy of SCL7A11 and GLUT1 Inhibition in Triple-Negative Breast Cancer via a GSH/ATP Dual-NIR-Responsive Fluorogenic Sensor

Triple-negative breast cancer (TNBC) lacks receptor expression and exhibits metabolic heterogeneity, leading to ineffective targeted therapy and chemotherapy resistance. There is an urgent need to investigate its metabolic reprogramming mechanisms and develop targeted intervention strategies. In TNBC, the overexpression of a solute carrier family member (SLC7A11) and glucose transporter 1 (GLUT1) drives tumor cell proliferation and survival through excessive glutathione (GSH)/adenosine triphosphate (ATP) production. Whether combined inhibition of SLC7A11 and GLUT1 produces synergistic antitumor effects via oxidative stress and energy imbalance and how GSH/ATP levels change remain unclear. We constructed the first near-infrared dual-activation probe M1219, which successfully visualized the regulatory relationship between oxidative stress and energy imbalance under the stimulation of sulfasalazine (SAS, SLC7A11 inhibitor) and rapamycin A (RgA, GLUT1 inhibitor) by real-time monitoring of the dynamic changes of GSH/ATP in cells. For the first time, we elucidated the NADPH/G6PD/GPX4/ACSL4 axis-mediated metabolic regulatory network under dual-target inhibition. Leveraging the tumor microenvironment’s GSH/ATP-specific activation mechanism, M1219 achieved the in vivo visualization of therapeutic efficacy in TNBC mice, validated the enhanced antitumor effect of the combined inhibition strategy, enabled precise resection of TNBC infiltration boundaries (negative margin of <0.1 mm), and successfully distinguished tumor tissue from marginal tissue in clinically resected breast cancer specimens.