Adherens junction protein expression is associated with poor response to neoadjuvant FLOT chemotherapy and pro‐inflammatory tumor microenvironment in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) demonstrates poor survival rates despite multimodal treatments, with significant inter-patient variability in response to standard pre-/perioperative therapies. This study investigates the relationship between adherens junction (AJ) protein expression in pre-treatment biopsies and response to neoadjuvant therapies in EAC. Mass spectrometry-based proteomics was performed on diagnostic biopsies from 157 EAC patients who subsequently received either perioperative FLOT chemotherapy or neoadjuvant CROSS radiochemotherapy. Protein expression profiles were analyzed with emphasis on AJ components. Findings were correlated with treatment response and histopathological parameters. We identified a distinct protein cluster enriched for AJ components that significantly correlated with response to FLOT chemotherapy. Among FLOT major responders, 94% exhibited high AJ expression. Low AJ expression occurred across histological subtypes, with varying frequencies: 27% in tubular-intestinal, 40% in mixed-type, and 50% in diffuse carcinomas. Low AJ expression was significantly associated with a pro-inflammatory tumor microenvironment and extracellular matrix (ECM) remodeling. AJ protein expression represents a potential predictive parameter for FLOT chemotherapy response in EAC and defines distinct phenotypes. The association between reduced AJ expression and inflammatory features suggests these tumors may represent candidates for further investigation of targeted therapeutic approaches, though the role of immunotherapy in this context remains to be determined. Pre-treatment AJ assessment could guide therapy selection to avoid ineffective therapies.