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

Reprogramming of energy metabolism plays pivotal roles in cancer progression and immune surveillance. Here, we demonstrated that hypoxic cancer cell secretome and breast cancer stem cell (BCSC) secretome similarly promoted the global reprogramming of metabolic pathways, particularly glycolysis, in normoxic cancer cells. Screening of BCSC secretome identified MIF as a pivotal factor potentiating glycolysis via transcriptional activation of ALDOC expression by MYC. Targeting MIF attenuated glycolysis as well as impaired tumor growth and metastasis. Cell-intrinsic MIF depletion in breast cancer augmented intratumoral cytolytic CD8+ T cells and pro-inflammatory macrophages while decreased tumor-associated neutrophils. Targeting MIF improved anti-PD-L1 immune checkpoint therapy of triple-negative breast cancer cells. Hence, this study presented a paradigm of heterocellular metabolic communication in modulating tumor energy metabolism and immune surveillance, and thereby proposes strategies to ameliorate immunotherapy in breast cancer. Samples consisting of three dissociated tumors were sorted for the CD45+ immune cell population to scRNA-seq data analysis, and each group was represented by two biologically independent samples from wild-type and Mif-depleted 4T1 tumors derived BALB/c mice.