Here, using the TNBC PDXs established and maintained in mice (Liu et al., 2010; Liu et al., 2019), human cell lines, and mouse tumor models with genetic modulations such as knockdown (KD) and knockout (KO), we examined the importance of CD81 in TNBC progression with a novel mechanistic link to CD44 interactions and self-renewal which is enhanced by uptake of cancer exosomes and coupled with endocytosis and metabolic pathways, and identified previously unknown tumor-intrinsic functions of CD81 in promoting tumor clustering and lung metastasis. This evidence concerns the gene CD44 and cancer.