化疗是对结肠直肠癌（CRC）的一种重要的临床治疗方式。由转运蛋白介导的异常药物外流作为肿瘤细胞获取化疗抵抗力的关键途径。越来越多的证据表明，肿瘤相关巨噬细胞（TAMs）在肿瘤发生和药物抵抗方面起着重要作用。然而，TAMs调控药物外流的具体机制仍然不清楚。在这里，我们发现TAMs通过细胞间互作介导的MRP1依赖性药物外流过程，使CRC细胞对5-氟尿嘧啶（5-FU）治疗具有抵抗力。机制上，TAM分泌的C-C基序趋化因子配体17（CCL17）和CCL22通过膜受体CCR4激活CRC肿瘤细胞中的PI3K/AKT通路。具体地，AKT的磷酸化失活了IP3R并在内质网中引起钙离子聚集，进而激活ATF6并上调GRP78的表达。相应地，过量的GRP78可以与MRP1相互作用并促进其向细胞膜转位，导致TAM诱导的5-FU外流。综上所述，我们的结果表明，TAMs通过上调GRP78表达促进MRP1的膜转位和药物外流，从而促进CRC化疗抵抗力，为TAM引起的药物抵抗提供了直接证据。© 2023. 作者。

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.© 2023. The Author(s).