These data establish that CXCL12 signaling through receptors CXCR4 and ACKR promotes the dissociation of β-arrestin 2 from PKM2 in a breast tumor environment, pointing to a mechanism by which CXCL12 signaling pathways may regulate functions of PKM2 in cancer and promote the growth of breast tumors. Here, CXCL12 is linked to breast neoplasm.