A fibroblast–myeloid niche supports stress adapted residual oesophageal adenocarcinoma after neoadjuvant chemotherapy

Treatment resistance in oesophageal adenocarcinoma (OAC) remains poorly defined. We used integrated single-cell and single-nucleus transcriptomic data to identify 5 conserved malignant epithelial programmes in primary OAC, and mapped their spatial organisation in matched pre-treatment biopsies and post-FLOT resection specimens using CosMx spatial transcriptomics. Chemotherapy was associated with depletion of an immune-primed programme, and enrichment of proliferative and stress adapted programmes, while programme-dominant cancer cells showed non-random spatial organisation. Residual cancer cells were recurrently embedded within a cancer–MyoCAF–myeloid niche. Predicted ligand–receptor analysis implicated shared but programme-specific stromal and immune signalling axes, including EGFR, HGF/MET, NOTCH, WNT and TGF-β pathways. Cancer cells within this niche showed attenuated epithelial differentiation and increased stress signalling. These findings define a spatially organised fibro-inflammatory ecosystem in residual OAC and suggest that therapy resistance reflects both malignant cell plasticity and microenvironmental niche support.