Resistance to systemic therapy remains the defining challenge in the management of gastric cancer (GC) and esophageal adenocarcinoma (EAC). While genomic drivers of resistance are well characterized, traditional bulk profiling has failed to capture the physical rules governing tumor survival within the complex tissue ecosystem. Emerging data from 2024–2025, leveraging high-resolution spatial transcriptomics and multi-omics, have recontextualized resistance as a phenomenon of “spatial privilege” rather than solely an intrinsic cellular fate. This review summarizes recent evidence to define “architectural refuges”: distinct spatial niches that physically shield malignant clones from cytotoxic and targeted agents. We delineate three critical resistance domains common to upper gastrointestinal adenocarcinomas: (1) The “Excluded” Niche, where specific cancer-associated fibroblast (CAF) subpopulations (iCAFs vs. myCAFs) and stiffened extracellular matrix create hypovascular zones that limit drug delivery; (2) the “Immune-Tolerant” Niche, characterized by the spatial exclusion of CD8+ T cells and the recruitment of suppressive myeloid populations via the MIF/CD74 and USP14 axes; and (3) the “Metabolic” Niche, where mitochondrial heterogeneity and lipid metabolic symbiosis establish nutrient-deprived niches that select for stem-like, dormant states. By mapping these conserved spatial determinants from primary GEJ tumors to peritoneal and distant metastases, we argue that overcoming resistance requires an advancement: moving beyond targeting individual mutations to dismantling the multicellular architecture that sustains malignancy.

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor patient outcomes and limited therapeutic options. WEE1, a G2/M checkpoint kinase, is often upregulated in cancers and associated with resistance to therapy. In this study, we identify a previously unrecognized cytoplasmic role of WEE1 in stabilizing the oncogenic transcription factor MYC and promoting drug resistance in EAC. WEE1 was found to be aberrantly overexpressed and mislocalized to the cytoplasm in EAC cell lines and patient samples. WEE1 depletion or inhibition by MK-1775 significantly reduced MYC protein levels and transcriptional activity by promoting proteasome-mediated degradation. Mechanistically, WEE1 inhibition activated GSK3β, leading to phosphorylation of MYC at threonine 58 and subsequent ubiquitin-dependent degradation. In contrast, overexpression of wild-type WEE1, but not a kinase-dead mutant (K328A), increased p-CDC2 (Y15) and MYC protein levels, confirming that WEE1's kinase activity is essential for maintaining MYC stability. WEE1 inhibition also downregulated the MYC-ABCC1 axis, decreased MRP1 expression, and impaired drug efflux. A high-throughput screen of 892 FDA-approved compounds identified the histone deacetylase inhibitor Panobinostat as a potent synergistic partner of MK-1775. Combination treatment induced robust apoptosis and markedly suppressed tumor growth in EAC organoids and patient-derived xenograft models. These findings reveal a novel cytoplasmic function of WEE1 in sustaining MYC stability and chemoresistance. Targeting WEE1 destabilizes MYC and enhances therapeutic response, supporting the combination of MK-1775 and Panobinostat as a promising treatment strategy for EAC.