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Deficiency of DNA repair pathways drives the development of colorectal cancer. However, the role of the base excision repair (BER) pathway in colorectal cancer initiation remains unclear. This study shows that Nei-like DNA glycosylase 1 (NEIL1) is highly expressed in colorectal cancer (CRC) tissues and associated with poorer clinical outcomes. Knocking out neil1 in mice markedly suppresses tumorigenesis and enhances infiltration of CD8+ T cells in intestinal tumors. Furthermore, NEIL1 directly forms a complex with SATB2/c-Myc to enhance the transcription of COL17A1 and subsequently promotes the production of immunosuppressive cytokines in CRC cells. A NEIL1 peptide suppresses intestinal tumorigenesis in Apc Min/+ mice, and targeting NEIL1 demonstrates a synergistic suppressive effect on tumor growth when combined with a nuclear factor κB (NF-κB) inhibitor. These results suggest that combined targeting of NEIL1 and NF-κB may represent a promising strategy for CRC therapy. [Display omitted] • Upregulation of NEIL1 enhances CRC initiation • NEIL1 directly form a transcriptional complex with SATB2/c-Myc/RNAPII • NEIL1 promotes COL17A1 expression leading an immunosuppressive microenvironment in CRC • Inhibition of NEIL1 can sensitize CRC cells to cytotoxic T cells Cao et al. report that NEIL1 drives CRC initiation through promoting the transcriptional level of COL17A1 and cytokine production of CRC cells via directly forming a complex with SATB2/c-Myc/RNAPII, which provides a link between carcinogenic inducers like oxidative stress, inflammation, and CRC initiation. [ABSTRACT FROM AUTHOR]