IGF2-associated tumor cells and APOE-positive macrophages define an imatinib resistance-associated niche in gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are highly responsive to imatinib, but acquired resistance frequently develops. In particular, the roles of distinct tumor cells and their interactions with tumor-associated macrophages (TAMs) in shaping imatinib response remain poorly understood. METHODS: We used integrative single-cell transcriptomic analysis to characterize tumor cells and tumor microenvironment heterogeneity in gastric GIST, with validation in independent imatinib-treated, metastatic, and spatial transcriptomic datasets. Cell-cell communication, metabolic pathway, in silico perturbation, and connectivity analyses were performed to identify resistance-associated microenvironmental programs. RESULTS: We identified five transcriptionally distinct GIST tumor-cell states with distinct functional programs. Among them, the S100A6-associated and IGF2-associated states showed opposing associations with imatinib response and distinct relationships with TAM programs. A niche comprising S100A6-associated tumor cells and CCL4-positive TAMs was observed in imatinib-sensitive tumors and exhibited stress-response and immune-activation features. In contrast, the IGF2-associated state was enriched in imatinib-resistant and metastatic GIST samples and showed coordinated occurrence with APOE-positive TAMs in a resistance-associated niche characterized by metabolic remodeling and immunoregulatory features, with predicted IGF and KIT signaling and iron-related metabolic crosstalk. This tumor-cell state also showed predicted immunosuppressive interactions with regulatory T cells. Integrative perturbation analysis identified a 61-gene resistance-associated signature, with IFI6 emerging as top-ranked candidate marker. CONCLUSIONS: These findings reveal distinct tumor-cell-macrophage niches underlying imatinib sensitivity and resistance in GIST, and identify the IGF2-associated GIST tumor-cell state-APOE-positive TAM axis as a candidate resistance-associated tumor-immune state with potential biomarker and therapeutic implications.