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

Abstract

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.