Autophagy Orchestrates Anti-Tumor Immunity to Enhance Chemosensitivity via the FBXW2/C/EBPβ/TIMP-2 Axis in Colorectal Cancer.

The efficacy of chemotherapy in colorectal cancer (CRC) is closely linked to its ability to remodel the tumor immune microenvironment (TIME), though the underlying molecular determinants remain incompletely defined. Here, we identified tumor-cell intrinsic autophagy as a pivotal orchestrator of an immunologically active TIME, essential for chemotherapy response. We demonstrated that 5-FU/Oxaliplatin treatment triggers autophagy-dependent TIMP-2 production, which restrains MMP-2/9 activity and promotes intra-tumoral accumulation of active CD8+ T cells. Disruption of this axis-through autophagy deficiency or loss of TIMP-2-leads to CD8+ T cell exclusion and therapeutic resistance. Conversely, restoration of TIMP-2 or co-administration of MMP-2/9 inhibitor successfully reinvigorated CD8+ T cells within the tumor and revived treatment efficacy. Mechanistically, autophagy-mediated degradation of FBXW2 leads to the accumulation of C/EBPβ via the ubiquitin-proteasome pathway, thereby driving transcriptional upregulation of TIMP-2. Clinically, autophagy status and TIMP-2 expression correlated with favorable immune profiles and improved clinical outcomes. These findings establish the autophagy-TIMP-2 axis as a key determinant of chemotherapy-induced immune remodeling and a potential target for enhancing therapeutic response and patient stratification in CRC.