Breast Cancer Stem Cells Regulated Metabolism Remodeling of Bulk Tumor Cells Drives Immune Evasion

Reprogramming of energy metabolism plays pivotal roles in cancer progression and immune surveillance. Here, we demonstrated that breast cancer cells showed positive feedback enhanced aerobic glycolysis in hypoxia condition. Further investigation suggested that breast cancer stem cells (BCSCs) induced by hypoxia stimulate aerobic glycolysis in bulk tumor cells. Cells cultured with hypoxic tumor cell- or BCSC-secretome exhibited similar gene expression patterns, with global remodeling of metabolism pathways, particularly glycolysis. BCSCs regulated glycolysis promoted breast cancer progression and evasion of immune surveillance. Screening of BCSC secretome identified MIF as a pivotal factor that potentiated glycolysis by increasing the expression of ALDOC. Breast cancer cell–intrinsic MIF depletion inhibited tumor progression and augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages. Targeting MIF optimized immune checkpoint therapy of breast cancer in both syngeneic mouse models and humanized mouse model. Hence, this study delineates the contribution of BCSC regulated bulk tumor cell glycolysis in immune surveillance; and thereby proposes strategies to optimize immunotherapy in breast cancer. MCF-7 cells were seeded with the regular medium in monolayer culture under normoxia or hypoxia condition for 48 hours. The conditioned medium was centrifuged at 4,000 g for 3 minutes and filtered with a 0.22 μm filter unit (Millipore) to deplete any cell debris. The MCF-7 cells were cultured with the CM derived from normoxia cells or hypoxia cells for 48 hours, and the RNA was isolated and sequenced.