Single-cell decoding of breast cancer organotropism: ecosystem mapping for precision therapy

Metastasis remains the primary cause of breast cancer death, driven by organotropism to brain, lung, bone, and lymph nodes. Single-cell and spatial multi-omics reveal organotropism as an active ecological process orchestrated by crosstalk between tumor cells and stromal/immune compartments. We synthesize advances into a unified framework: conserved programs (hypoxic memory, stemness, immune evasion) operate alongside organ-specific adaptations—lipid rewiring via RARRES2-PTEN-mTOR in brain, DLAT-mediated fatty acid oxidation in lung, TDO2 + fibroblast-kynurenine ferroptosis resistance in lung, IL-34-CSF1R-ARG1 + macrophage immunosuppression in brain, and MAF-CD248 dormancy in bone. These vulnerabilities inform therapies: dual-payload ADCs, metabolic blockers, and engineered EVs. We address limitations such as spatial mapping, dormancy models, translation and outline a roadmap with AI, liquid biopsies, and spatial profiling for precision interception. This Review advocates shifting from cytotoxic to niche-directed therapies, framing metastasis as an ecosystem challenge.