Triple‐Negative Breast Cancer Cells Utilize IL8 and CXCL1 to Suppress NK Cells’ Function and Facilitate Cancer Metastasis

ABSTRACT Triple‐negative breast cancer (TNBC) is the most aggressive breast cancer subtype with high metastatic potential and limited treatment options. Natural killer (NK) cells represent a promising immunotherapy strategy due to their innate tumor‐killing capacity, but their efficacy against TNBC remains limited. We found that TNBC cells, particularly the mesenchymal‐like subtype, exhibited greater resistance to NK cells compared to non‐TNBC cells. Mechanistic studies indicate that TNBC cells’ survival in response to NK cells occurs in three phases. First, within 1 h of NK cell co‐culture, TNBC cells accumulate reactive oxygen species (ROS), which upregulate C‐X‐C motif chemokine ligand 1 (CXCL1) and interleukin 8 (IL8) expression in an NF‐κB− and ERK/JNK−AP‐1‐dependent manner. Second, secreted CXCL1/IL8 binds to C‐X‐C motif chemokine receptor 1/2 (CXCR1/2), activating the AKT−BCL‐2 pathway to enhance cancer cell survival and suppress NK cell function by downregulating NKG2D, TRAIL, and IFN‐γ expression. Third, CXCL1/IL8−CXCR1/2 autocrine loop further amplifies their own synthesis and induces programmed cell death 1 ligand 1 (PD‐L1) expression via NF‐κB and ERK/JNK−AP‐1 pathways. High CXCL1/IL8 expression correlates with reduced NK cell infiltration and shorter distant‐metastasis‐free survival in breast cancer patients. Combinatorial application of CXCR1/2 inhibitor with anti‐PD‐L1 antibody can overcome NK cell dysfunction and reduce TNBC metastasis.