Single-cell and spatial multi-omics reveal a recurrent multicellular niche at the tumor-stroma interface in multidrug resistance

ABSTRACT: Multi-drug resistance (MDR) is an almost inevitable end point of cancer therapy, driving rapid tumor progression, yet its evolutionary logic remains unclear because MDR tumors are rarely resected. Using paired therapy-naive and MDR melanoma specimens from a clinical trial, integrated with single-cell and spatial multi-omics and evaluated together with datasets from ten additional cancer types, we identify a recurrent MDR-associated spatial nexus along the tumor-stroma interface. This niche juxtaposes CXCL14+ inflammatory cancer-associated fibroblasts (iCAFs), TREM2+ tumor-associated macrophages (TAMs), and AXL+ dedifferentiated tumor cells, and is accompanied by loss of tumor-reactive CXCL13+ CD8+ T cells. In vitro, CXCL14 promotes macrophage migration and TREM2 induction, while TREM2+ TAMs suppress CXCL13+ CD8+ T cells via CD86-CTLA4 signaling. TREM2+ TAMs also promote tumor dedifferentiation through oleic acid-driven GAS6-AXL activation. We develop an FAP/TREM2-targeting bispecific antibody to disrupt this spatial nexus and restore therapeutic sensitivity in MDR patient-derived xenograft models with favorable safety.

INSTRUMENT(S): MS Imaging - negative

PROVIDER: MTBLS15322 | MetaboLights | 2027-08-13

REPOSITORIES: MetaboLights