5‐FU Resistance Facilitates Immune Evasion in Esophageal Squamous Cell Carcinoma Through ADAM10‐Mediated PD‐L1 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.