Paclitaxel drives TREM2+ macrophage expansion underlying its inferior therapeutic efficacy compared to Nab-paclitaxel

By Joseph L. Watson, David Juergens, N. Bennett, Brian L. Trippe, Jason Yim, Helen E. Eisenach, Woody Ahern, A. J. Borst, R. Ragotte, L. Milles and 18 more. Nature Communications, 2026

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Paclitaxel and nab-paclitaxel differ in therapeutic efficacy and modulation of the tumor immune microenvironment, yet the molecular basis remains poorly defined. Here, based on a meta-analysis, we first show that treatment with nab-paclitaxel results in a higher overall response rate and pathological complete response compared to paclitaxel in female patients with breast cancer. Notably, TREM2 expression in macrophages is elevated in primary tumors of paclitaxel- but not nab-paclitaxel-treated female patients. In metastatic breast cancer, TREM2+ macrophage infiltration is increased in primary tumors. In breast cancer models in female mice, paclitaxel, but not nab-paclitaxel, promotes lung metastasis by recruiting TREM2+ macrophages to primary tumors. Mechanistically, paclitaxel enhances the ATF3-FGF2 axis in breast cancer cells; secreted FGF2 activates the EGR1-TREM2-EMT cytokine axis in macrophages. Genetic ablation of Trem2 or pharmacologic targeting with antisense oligonucleotides suppress paclitaxel-induced breast cancer lung metastasis in vivo. Collectively, our findings demonstrate that paclitaxel, but not nab-paclitaxel, stimulates TREM2 expression and expands TREM2+ macrophages, suggesting that TREM2 targeting could enhance paclitaxel efficacy while limiting metastasis.

Subfields: Immunology, Neurology

View Paper: https://www.semanticscholar.org/paper/dc2b1f10818ba574ecd06e323f77edf2dfd6c982

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