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.