5‐ <scp>FU</scp> Resistance Facilitates Immune Evasion in Esophageal Squamous Cell Carcinoma Through <scp>ADAM10</scp> ‐Mediated <scp>PD</scp> ‐ <scp>L1</scp> Shedding and Tumour Microenvironment Remodelling

Chemoresistance remains a major challenge in esophageal squamous cell carcinoma (ESCC) therapy, particularly resistance to 5-Fluorouracil (5-FU). This study uncovers how 5-FU resistance reprograms the tumour microenvironment, primarily through the up-regulation of ADAM10 and the release of soluble PD-L1, which collectively facilitate immune evasion. Using a 5-FU-resistant AKR mouse ESCC cell line (5-FU-AKR) and its parental counterpart, we applied third-generation DNA sequencing, proteomic analysis, and single-cell RNA sequencing to unravel the resistance-associated molecular and cellular shifts. We found that ADAM10 is significantly up-regulated in 5-FU-AKR cells, promoting soluble PD-L1 release, thereby limiting CD8+ T cell infiltration. Xenograft models further demonstrated enhanced tumourigenicity and immune exclusion in 5-FU-resistant tumours. These findings highlight a novel mechanism of immune suppression driven by ADAM10, suggesting that targeting the ADAM10-PD-L1 axis may restore anti-tumour immunity and improve treatment outcomes for 5-FU-resistant ESCC.