TICRR orchestrates mitochondrial dynamics and tumor-endothelial crosstalk to drive radioresistance in colorectal cancer

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Abstract Radiotherapy resistance remains a major challenge in the clinical management of colorectal cancer (CRC), highlighting the urgent need to identify novel regulators of radiosensitivity. Here, we reveal a multi-layered mechanism whereby TICRR drives CRC radioresistance. TICRR is significantly upregulated in radioresistant CRC tissues and cell lines and is associated with poor patient survival. TICRR knockdown suppresses tumor cell proliferation, impairs DNA damage repair, and enhances radiosensitivity both in vitro and in vivo. Mechanistically, TICRR functions as an RNA-binding protein (RBP) to stabilize the mitochondrial protein C1QBP mRNA, thereby maintaining mitochondrial function and regulating AMP levels, which in turn modulate the AMPK/HIF pathway and VEGFA transcription. TICRR-high tumor cells interact with endothelial cells via the VEGFA-VEGFR1 signaling axis and transfer mitochondria to endothelial cells to enhance angiogenesis, a process disrupted by TICRR downregulation. Collectively, these findings demonstrate that TICRR promotes CRC radioresistance through a multi-layered mechanism involving mitochondrial function and tumor-endothelial cell communication, highlighting TICRR inhibition as a potential strategy for radiosensitization.

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