M2-TAM-derived XCL2 suppresses paclitaxel sensitivity in triple-negative breast cancer by transcriptionally activating NEK2.

Abstract

Paclitaxel (PTX) resistance is a pivotal factor contributing to the poor prognostic outcome of patients with triple-negative breast cancer (TNBC). M2-type tumor-associated macrophages (M2-TAMs), a key component of the breast tumor microenvironment, foster chemoresistance through the release of multiple cytokines. The chemokine XC motif chemokine ligand 2 (XCL2) is significantly elevated in M2-polarized TAMs, but its role in PTX resistance remains unclear. Human THP-1 monocytes were first differentiated into M0 macrophages (PMA), followed by M2 polarization with IL-4 and IL-13, with polarization efficiency confirmed by flow cytometry. Cell viability and apoptosis were measured using the CCK-8 assay and flow cytometry, respectively. The binding relationship between transcription factor 4 (TCF4) and the never in mitosis gene A-related kinase 2 (NEK2) promoter was investigated by ChIP and dual-luciferase reporter assays. Our results showed that M2-TAM-secreted XCL2 reduced PTX-induced apoptosis and enhanced TNBC cell viability. Mechanistically, XCL2 was associated with XCR1 activation and subsequent β-catenin nuclear translocation, which may enable TCF4 to transcriptionally upregulate NEK2. As expected, TCF4 knockdown in TNBC cells reduced PTX resistance, while this effect was reversed by NEK2 overexpression. In addition, NEK2 knockdown in TNBC cells reversed the promoting effect of M2-CM on PTX resistance in TNBC. In vivo, M2-TAMs were associated with accelerated tumor growth under PTX treatment, whereas XCL2 knockdown restored PTX efficacy. To conclude, M2-TAM-derived XCL2 enhanced PTX resistance in TNBC cells by activating the β-catenin/TCF4/NEK2 pathway. Targeting this signaling may provide novel strategies to overcome PTX resistance in TNBC.