Immune-metabolic crosstalk in the pre-metastatic lung niche of breast cancer: challenges and therapeutic opportunities
Abstract
Breast cancer is the most common malignant tumor among women. Distant metastasis, particularly to the lungs, leads to low survival rates.Clinical follow-up reveals that a significant proportion of patients develop metastasis 5–10 years after diagnosis, indicating that metastatic planning occurs very early. In a modern extension of the “seed-soil” paradigm, the represents a susceptible ecological state established in target organs prior to the arrival of circulating tumor cells. Growing evidence indicates that the primary tumor pre-treats the lungs via soluble mediators, extracellular vesicles, and metabolic cues, increasing vascular permeability and remodeling the matrix to generate an immunosuppressive, metabolically dysregulated Pre-metastatic niche( PMN ) . Crucially, immune and metabolic programs interlock in a self-reinforcing positive feedback loop to sustain colonization. Within this immunometabolic feedback model framework, we synthesized common mechanisms, delineated subtype-specific biases (Luminal A, Luminal B, HER2 ⁺ , TNBC), and mapped therapeutic opportunities. We highlight actionable targets (MCT1/4, CD39/CD73-A2A, IDO1-AHR, CCR2/CSF1R), propose “ strong-weak ” combinations stratified on subtype frameworks, and discuss translational challenges including standardized readouts and early intervention windows. This framework provides a manageable pathway for preventing and intervening early in breast cancer lung metastasis. This narrative review may be of considerable value to researchers and clinicians working on cancer metastasis—particularly cancer biologists and translational scientists in breast cancer, as well as medical oncologists, pathologists, and methodologists focused on PMN biology and immunometabolic targeting.