Triple-Negative Breast Cancer Cells Utilize IL8 and CXCL1 to Suppress NK Cells' Function and Facilitate Cancer Metastasis.

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.