Esophageal squamous cell carcinoma (ESCC) represents a major therapeutic challenge due to the rapid development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Recent evidence highlights that this resistance is driven not only by genetic mutations but also by spatial heterogeneity of tumor microenvironments and compensatory signaling mechanisms. In this review, we propose a spatial-signaling-intervention framework with a particular focus on the NTRK2/MAPK signaling axis, which plays dual roles in signaling compensation and immune evasion. By integrating spatial multi-omics, proteomics, and AI-assisted topological modeling, three resistant niches are identified: (1) cancer stemness-enriched zones, (2) MAPK hyperactive islands, and (3) immune-cold regions. Based on this atlas, we design precision nanotherapeutic platforms, including responsive, dual-target, and feedback-loop nanocarriers, to selectively modulate resistant spatial niches. Preclinical validation in patient-derived xenografts and organoid models further demonstrates the translational potential of these strategies. This work provides a conceptual and technological roadmap for overcoming EGFR-TKI resistance in ESCC. Atlas-guided nanocarrier systems offer a promising avenue for spatially targeted and feedback-responsive therapy, highlighting the role of pharmaceutics in advancing precision oncology.