NEDD4L suppresses colorectal cancer metastasis and immune escape by inhibiting STAT3 signaling.

BACKGROUND

NEDD4L plays key roles in regulating cancer progression; however, its function in colorectal cancer (CRC) remains poorly understood. This study aimed to investigate the biological functions of NEDD4L in CRC and the underlying mechanisms.

METHODS

NEDD4L expression in CRC was analyzed using public databases and paired human CRC tissues. Survival analysis was performed to evaluate the clinical significance of NEDD4L, and its correlation with the tumor microenvironment (TME) was explored. The effects of NEDD4L on CRC cell behaviors were assessed using CCK-8, transwell, and wound healing assays. Western blotting and in vivo experiments were conducted to elucidate the molecular mechanisms of NEDD4L in CRC. Finally, the role of NEDD4L in modulating immunotherapy responses was investigated using an MC38 tumor model.

RESULTS

NEDD4L is downregulated in CRC tissues, and its low expression is significantly associated with poor prognosis in CRC patients. NEDD4L expression correlates with immune cell infiltration in CRC, particularly with infiltrating CD8⁺ T cells. Functional experiments demonstrated that NEDD4L inhibits CRC cell migration without affecting proliferation in vitro. In vivo studies revealed that NEDD4L overexpression significantly suppresses tumor growth by promoting CD8⁺ T cell recruitment. Mechanistically, NEDD4L inhibits immune evasion in CRC by suppressing the STAT3/PD-L1 axis. Additionally, NEDD4L overexpression enhances the efficacy of immunotherapy in CRC models.

CONCLUSION

NEDD4L is downregulated in CRC and associated with the dysregulation of the TME. NEDD4L overexpression could inhibit CRC metastasis and immune evasion by repressing STAT3 signaling, suggesting that it is a potential target for improving CRC treatment efficacy.