Abstract
Cancer cells exhibit altered metabolism and energetics, prominently reprogramming lipid metabolism to support tumor growth and progression, making it a promising target for cancer therapy. However, traditional genetic and pharmaceutical approaches for disrupting lipid metabolism face challenges due to the adaptability of tumor metabolism and potential side effects on normal tissues. Here, we present a bacteria-based bioorthogonal platform combining transition metal catalysts and Lactobacillus to disrupt the flexible lipid homeostasis in tumors. This platform activates glutamine transporter inhibitors in situ, targeting lipid synthesis in hypoxic tumor environments, while Lactobacillus inhibits lipid accumulation. By disrupting lipid metabolism and glutamine utilization, the present study proposes a safe and potent strategy for cancer therapy, with potential applications for other metabolic diseases.