Fibrotic mechanobiological microenvironments drive mechano-immune exclusion and immunotherapy resistance in breast cancer: mechanisms, stratification and therapeutic opportunities.

The clinical benefit of immunotherapy in breast cancer has moved from metastatic triple-negative breast cancer (TNBC) into earlier-stage high-risk disease, but primary resistance, acquired resistance and non-durable responses remain frequent. Programmed death-ligand 1 (PD-L1), tumour-infiltrating lymphocytes (TILs), tumour mutational burden and antigen-presentation capacity capture important features of immune priming, but do not fully explain why some tumours contain immune cells yet fail to respond. Here, we refine the concept of the mechano-immune exclusion phenotype (MIEP), a spatially defined and mechanistically testable state in which fibrotic extracellular matrix (ECM) remodelling, collagen crosslinking and alignment, cancer-associated fibroblast (CAF) activation, tissue stiffening, solid stress and impaired perfusion restrict effector-cell access to tumour nests and reduce local cytotoxic function. We distinguish MIEP from established immune-excluded, TGF-β-stromal, ECM-suppression and CAF-evasion frameworks, and propose that it should be treated as a mechanistic sublayer of immune exclusion rather than as a replacement for existing immune phenotypes. We review the ECM-CAF-vascular-metabolic-immune axis, its effects on immune-checkpoint blockade, adoptive cell therapy and nanomedicine delivery, and the current clinical evidence linking stromal and mechanical biomarkers with immunotherapy response. We further discuss practical biomarker implementation, clinical trial readiness, combination-toxicity risks and validation requirements. A clinically useful MIEP framework will require prospective cohorts, standardized collagen/stiffness/CAF thresholds and spatially resolved endpoints that test whether stromal normalization truly improves immune-cell access and therapeutic response.