Hematopoietic Stem Cells Modulate Tumor Immune-Environment to Target Triple-Negative Breast Cancer via Altering Mitochondrial Bioenergetics

Ontogenic development of Hematopoietic stem cells (HSCs) takes place at diverse anatomical niches. Moreover, during embryonic development, HSCs migrate from the aorta-gonad mesonephros (AGM) to the fetal liver and finally to the bone marrow immediately after childbirth. Hence, the primary residence of adult HSCs in the bone marrow continues replenishing the hematopoietic lineage pool. In vivo, the HSC niche is significant and might be harnessed in regenerative medicine. HSCs in various niches have exhibited their respective tropism and proliferations based on the growth factors secreted by the niche. Accordingly, in this work, we hypothesized HSCs tropism towards cancer and stem cell niche of triple-negative breast cancer (TNBC) and HER2+, having a high relapse rate for possible cell therapy development. Our results indicate that HSC exclusive tropism towards breast cancer stem cells (CSC) and interaction with the cancer milieu lead to HSC differentiation into T-lymphocyte cells (CD4 & CD8). Moreover, the single-cell type proteomics of the migrated HSCs towards TNBC-CSCs and HER2+ cells indicated upregulation of IL-7 and Notch protein and several other upregulated proteins primarily involved in T cell activation and migration-related pathways. Likewise, the metabolomics from HSCs-derived conditioned media-treated CSCs, and HER2+ cells showed the capability of HSC-CM in arresting the growth and cell cycle of TNBC-CSC via altered mitochondrial bioenergetics. Hence, this study paves the way toward harnessing the potential of both HSCs and HSC-CM for personalized medicine against TNBC CSCs. HighlightsO_LIHematopoietic stem cells exhibited tumor tropism towards triple negative breast cancer stem cells and HER2+ cancer cells. C_LIO_LIUpon migration in the tumor milieu, HSCs differentiated into T cells, targeted CSCs, and modulated the upregulation of interleukin-7 and notch proteins. C_LIO_LIHSCs-CM inhibited the cell cycle in TNBC-CSCs by downregulating CDK1, disrupting mitochondrial bioenergetics via upregulated Drp1, and inducing CSC apoptosis. C_LIO_LIParacrine signaling from HSCs via conditioned media induced metabolic stress and disrupted key metabolic pathways in TNBC-CSCs. C_LI SummaryHematopoietic stem cells (HSCs) are known for their regenerative potential in the blood system. This study reveals the novel therapeutic potential of hematopoietic stem cells (HSCs) in combating triple-negative breast cancer stem cells (TNBC-CSCs). HSCs exhibited tropism towards TNBC-CSCs, themselves differentiated into T cells within the tumor microenvironment, leading to targeted cell killing of TNBC-CSCs. In addition, paracrine signaling from HSC-conditioned media (CM) induced metabolic stress in TNBC-CSCs and disrupted key metabolic pathways. HSC-CM also disrupted mitochondrial dynamics and function, leading to DNA damage and apoptosis. Critically, HSC-CM impaired TNBC-CSC stemness by downregulating stemness genes, leading to the inhibition of 3D spheroid formation. Hence, our study highlights HSCs as a promising therapeutic strategy for targeting TNBC-CSCs via disrupted metabolic homeostasis and self-renewal.