LAT1 Promotes Immunosuppression in Cervical Cancer by Interacting with TRIM67 to Facilitate IRF3 Ubiquitination and Degradation.

Cervical cancer (CC) is characterized by tumor immune escape, which underlies suboptimal therapy responses and an increased recurrence risk. Despite the established role of LAT1 in cancer progression, its regulatory mechanism in the CC immune microenvironment remains elusive. LAT1 expression in cervical squamous cell carcinoma and its correlation with CD8+ T cell infiltration were assessed through the bioinformatic approach. LAT1 mRNA and protein expression were examined by qRT-PCR and Western blot, respectively. In a co-culture system with CC cells, CD8+ T cell antitumor activity was measured by lactate dehydrogenase release, ELISA, CCK-8, colony formation, and flow cytometry. The LAT1/TRIM67 interaction was identified through bioinformatics and validated by Co-IP and immunofluorescence. Potential ubiquitination substrates of TRIM67 were screened through bioinformatics. CHX chase assays combined with ubiquitination analysis were employed to verify the IRF3 degradation pathway. Finally, in vivo functional validation was conducted in a mouse xenograft model. LAT1 was overexpressed in CC tissues and cell lines. LAT1 expression negatively correlated with CD8+ T cell infiltration. LAT1 knockdown enhanced CD8+ T cell antitumor activity. Mechanistically, LAT1 suppressed CD8+ T cell antitumor function in CC by interacting with TRIM67 to promote ubiquitination and degradation of IRF3. LAT1 recruits TRIM67 to mediate IRF3 ubiquitination and degradation, ultimately suppressing CD8+ T cell function and promoting immune escape. These findings provide a theoretical basis for targeting the LAT1/TRIM67 axis to enhance immunotherapy in CC.