Glycosylated extracellular matrix drives immune suppression by modulating macrophage-T cell crosstalk in triple-negative breast cancer

Abstract

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 use comprehensive multi omics profiling of triple-negative breast cancer (TNBC), an aggressive and treatment-resistant subtype, to investigate this issue. We report 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 modifies the tumor immune microenvironment. This modification reprograms tumor-associated myeloid cells toward an immunomodulatory phenotype and improves infiltration of T cells. Notably, ECM desialylation alters selectin and selectin-ligand programs on T cells, consistent with improved trafficking and intratumoral access. In parallel, macrophage–T cell interactions are reshaped, leading to reduced T cell exhaustion. Our findings identify ECM glycan modifications as critical regulators of the innate and adaptive TNBC immune microenvironment. They suggest that targeting ECM glycosylation could offer potential strategies to boost anti-tumor immunity in this aggressive breast cancer subtype.