Collagen-bearing exosomes from breast cancer-associated fibroblasts promote T cell dysfunction

Cancer-associated fibroblasts (CAFs), a major component of the breast tumor microenvironment, drive immune evasion in various cancers by promoting T cell exclusion and dampening T cell activation. Previous studies have implicated CAF-derived soluble factors in mediating these immunosuppressive effects. Here, we investigated whether exosomes secreted by CAFs could suppress T cell activity. Inhibition of global exosome secretion in breast tumor-bearing mice significantly reduced tumor growth and increased tumor-infiltrating T cells with lower exhaustion marker expression. Conversely, administration of CAF-derived exosomes into tumors produced the opposite effects. Moreover, CAF exosomes associated with T cells in vivo and impaired T cell activation and cytotoxic potential in ex vivo assays. Proteomic and biochemical analyses of T cells exposed to CAF exosomes revealed dampened early T cell receptor signaling. Mass spectrometry identified an extracellular matrix signature on CAF exosomes. Depleting Type I and Type V collagens from CAF exosomes restored T cell proliferation, while overexpression of collagen in cancer cells led to its incorporation into exosomes, which suppressed T cell activation. These findings suggest that a signaling bridge between CAF exosomes and T cells, mediated by collagen, promotes T cell dysfunction, contributing to immune evasion in breast cancer.