Activity-Based Bioluminescent\nLogic-Gate Probe Reveals\nCrosstalk Between the Inflammatory Tumor Microenvironment and ALDH1A1\nin Cancer Cells

Cancer cells with high expression of aldehyde dehydrogenase\n1A1\n(ALDH1A1) are more resistant to chemotherapy, contribute to tumor\nprogression, and are associated with poor clinical outcomes. ALDH1A1\nplays a critical role in protecting cells from reactive aldehydes\nand, in the case of stem cells, regulates their differentiation through\nthe retinoic acid signaling pathway. Despite the importance of this\nenzyme, methods to study ALDH1A1 high-expressing cancer cells in vivo\nremain limited. In this work, we developed AlDeLuc, the first logic-gated\nbioluminescence probe designed to selectively evaluate ALDH1A1 activity\nin tumor cells. The probe is sequentially activated by acidic intracellular\ncompartments (i.e., endosomes) and ALDH1A1, ensuring precise detection\nof ALDH1A1 high-expressing cells and minimizing off-target detection\nof non-ALDH1A1 cells. Beyond demonstrating efficacy in multiple cancer\ncell lines and a murine model of breast cancer, we employed AlDeLuc\nto investigate how the population of ALDH1A1 high-expressing cells\nis influenced by the inflammatory status of a tumor in the context\nof a high-fat diet. These findings establish a molecular link between\nobesity, inflammation, and tumor progression.