Spatial immune ecosystems govern therapeutic response in HER2-low breast cancer

HER2-low breast cancer represents a clinically important but biologically heterogeneous disease state, and the spatial immune programs underlying therapeutic response remain poorly understood. Here, we used single-cell spatial transcriptomics to characterize HER2-low and HER2-high breast tumors and define microenvironmental features associated with treatment sensitivity and resistance. We identified diverse malignant, stromal, and immune compartments, with dendritic cells emerging as a highly remodeled population in HER2-low tumors. Focused analysis resolved distinct dendritic-cell states, including homeostatic cDC2, IFN-activated mature cDC, classical functional cDC2, plasmacytoid DC, and ITGAX-positive monocyte-derived DC populations. Spatial proximity analysis further revealed that resistant HER2-low tumors exhibited increased segregation of tumor epithelial cells from effector immune populations and enrichment of myeloid-rich immune niches, consistent with an immune-restricted spatial architecture. Independent TCGA-BRCA validation confirmed the clinical relevance of these dendritic-cell states, with elevated homeostatic cDC2 signatures predicting poor survival, whereas inflammatory dendritic-cell signatures were associated with favorable outcomes. Resistant HER2-low tumors were characterized by enrichment of homeostatic and classical cDCs, depletion of IFN-activated cDCs and pDCs, altered tumor–myeloid–T-cell communication, and expansion of spatially organized resistant niches, whereas sensitive tumors retained immune-intermixed niches enriched for antigen presentation and effector immune interactions. Together, these findings demonstrate that therapeutic resistance in HER2-low breast cancer is driven by coordinated spatial remodeling of dendritic-cell states and immune architecture, identifying dendritic-cell–myeloid niche organization as a potential biomarker and therapeutic vulnerability.