Residual cancer burden (RCB) is a strong prognostic marker after neoadjuvant chemotherapy (NAC) in breast cancer (BC), yet some BCs defy their predicted outcomes. Using single-cell spatial transcriptomics and genomic profiling, we investigate mechanisms underlying divergent fates of BCs with high RCB across subtypes. In triple-negative BC (TNBC), CXCL9+ macrophage-CD8 T cell interactions via chemokines and interferon-gamma signaling promote favorable outcomes, while SPP1+ macrophage-cancer cell interactions driven by hypoxia signaling correlate with poor prognosis. In non-TNBC, the extent of basal-like cancer cells and their proximity to scarce immune cells are linked to prognosis. Additionally, tumor-intrinsic features-such as homologous recombination deficiency in hormone receptor (HR)-positive cancers and structural variations, including extrachromosomal ERBB2 DNA in human epidermal growth factor receptor 2 (HER2)-positive cancers-predict worse outcomes. This study highlights distinct genomic and microenvironmental strategies governing BC subtype-specific fates after NAC.