Abstract
Acquired resistance to oxaliplatin (Oxa) represents a major clinical challenge in the treatment of colorectal cancer (CRC). Lysosomes are intracellular degradative organelles that enable cancer cells to adapt to metabolic and environmental stress; however, their precise regulatory roles in drug resistance remain poorly understood. Here, we report that lysosomal damage and its selective autophagic clearance (lysophagy) occur frequently in both Oxa-treated CRC cells and Oxa-resistant (OxaR) CRC cells. Through quantitative proteomics, we identified the significant downregulation of mitochondrial transcription factor A (TFAM) as a key event in Oxa-treated and OxaR cells. Mechanistically, Oxa-induced TFAM loss leads to mitochondrial DNA (mtDNA) leakage into the cytosol, which activates the STING-TBK1 signaling axis. This pathway subsequently enhances lysophagic flux, providing cancer cells with a survival advantage under Oxa stress. Crucially, pharmacological inhibition of TBK1 abrogates this adaptive lysophagy, restoring Oxa sensitivity and suppressing tumor growth in both xenograft and patient-derived organoid models. Collectively, our study reveals a novel TFAM-mtDNA-STING-TBK1 signaling axis that promotes chemoresistance through the co-option of lysophagy, highlighting TBK1 as a viable therapeutic target to overcome Oxa resistance in CRC.