Glycosylated extracellular matrix drives immune suppression by controlling T cell movement, macrophage phenotype, and macrophage-T cell crosstalk in triple negative breast cancer

Abstract The tumor extracellular matrix (ECM) is increasingly recognized as a key driver of immune suppression and therapy resistance in cancer. However, the specific ECM components and mechanisms that create this immunosuppressive environment remain poorly understood, hindering the development of new therapies. Here, we focus on triple-negative breast cancer (TNBC), an aggressive and treatment-resistant subtype, and use comprehensive multi-omics profiling of TNBC tissues to investigate this issue. We find that ECM immunomodulation in TNBC is mediated by post-translational glycan modifications on ECM proteins. Using decellularized human TNBC samples, we show that targeted enzymatic removal of these ECM glycans dramatically reprograms the tumor immune microenvironment. This modification shifts tumor-associated myeloid cells towards an activated phenotype, restores infiltration of cytotoxic T cells, and in tumor cells lowers expression of genes linked to epithelial–mesenchymal transition (EMT). Consequently, these changes alter interactions between macrophages and T cells, which leads to reduced T cell exhaustion and increased activation. Our findings identify ECM glycan modifications as critical regulators of the TNBC microenvironment. They suggest that targeting ECM glycosylation could offer novel strategies to boost anti-tumor immunity in this aggressive breast cancer subtype.