Natural killer (NK) cell-based therapies show great promise for treating triple-negative breast cancer (TNBC). However, in the tumor microenvironment, some TNBC cells develop resistance to NK cell-mediated killing and contribute to NK cell exhaustion. In this study, TNBC cell populations are isolated that can resist NK cell attacks and uncovered the underlying mechanisms. It is found that these resistant TNBC cells secrete high levels of interleukin-11 (IL-11). IL-11 acts through a process known as trans-signaling by forming complexes with the soluble IL-11 receptor (sIL-11R) and engaging the gp130 receptor on NK cells. This trans-signaling activates the JAK1/STAT1/3 pathway, leading to the upregulation of p21 and subsequent cell cycle arrest in NK cells. As a result, the proliferation and IFNγ production of NK cells are inhibited, enabling TNBC cells to resist NK cell-mediated killing. Disrupting IL-11 or sIL-11R in TNBC cells restores NK cell activity. Importantly, it is also found that IL-11 expression is elevated in human TNBC tissues and negatively correlated with the number of NK cells in the tumor microenvironment. These findings identify IL-11 trans-signaling as a novel mechanism of immune evasion in TNBC and suggest that targeting this pathway may enhance the effectiveness of NK cell-based therapies.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.