Abstract Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p‐eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X‐ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio‐resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X‐ray irradiation is key for the elevated expression of p‐eIF2α and ATF4, and therefore radio‐resistance. This finding guided to discover that metformin and 2‐DG are synergistic in reversing radio resistance by inhibiting p‐eIF2α and ATF4. Liposomes loaded with metformin and 2‐DG (M/D‐Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio‐resistance and preventing T lymphocyte exhaustion.
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