Tumor-associated macrophages promote chemoresistance to Paclitaxel via activating NOTCH2-JAG1 juxtacrine signaling

Fazhi Yu; Qin Zhou; Weiqiang Yu; Tong Zhou; Cheng Cao; Yijia Xie; Peng Zhang; Hanyuan Liu; Wei He; Aoxing Cheng; Xiaopeng Ma; Qingfa Wu; Qi Zhao; Jing Guo; Kaiguang Zhang; Ying Zhou; Jue Shi; Zhenye Yang

doi:10.1186/s12943-025-02546-w

Tumor-associated macrophages promote chemoresistance to Paclitaxel via activating NOTCH2-JAG1 juxtacrine signaling

Mol Cancer. 2026 Jan 10. doi: 10.1186/s12943-025-02546-w. Online ahead of print.

Authors

Fazhi Yu^#^{1

2}, Qin Zhou^#², Weiqiang Yu², Tong Zhou², Cheng Cao³, Yijia Xie², Peng Zhang², Hanyuan Liu⁴, Wei He⁵, Aoxing Cheng², Xiaopeng Ma⁶, Qingfa Wu², Qi Zhao⁷, Jing Guo⁸, Kaiguang Zhang⁹, Ying Zhou¹⁰, Jue Shi¹¹, Zhenye Yang^{12

13

14

15}

Affiliations

¹ Department of Digestive disease, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China.
² State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ Center for Reproduction and Genetics, Department of Obstetrics and Gynecology, Division of Life Sciences and Medicine, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
⁴ Department of Obstetrics and Gynecology, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China.
⁵ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA.
⁶ Department of General Surgery, the First affiliated hospital of University of Science and Technology of China, Anhui Provincial Hospital, Hefei, China.
⁷ MoE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China.
⁸ Department of Digestive disease, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China. jguo2013@ustc.edu.cn.
⁹ Department of Digestive disease, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China. zhangkaiguang@ustc.edu.cn.
¹⁰ Department of Obstetrics and Gynecology, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China. caddiezy@ustc.edu.cn.
¹¹ Center for Quantitative Systems Biology, Department of Physics, Hong Kong Baptist University, Hong Kong, China. jshi@hkbu.edu.hk.
¹² Department of Digestive disease, Division of Life Sciences and Medicine, the First affiliated hospital of USTC, University of Science and Technology of China, Hefei, China. zhenye@ustc.edu.cn.
¹³ State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. zhenye@ustc.edu.cn.
¹⁴ Institute of Cancer Research, Anhui Key Laboratory of Molecular Oncology, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, PR China. zhenye@ustc.edu.cn.
¹⁵ Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. zhenye@ustc.edu.cn.

^# Contributed equally.

PMID: 41519773
DOI: 10.1186/s12943-025-02546-w

Abstract

Background: Taxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet the underlying molecular mechanisms are poorly understood.

Methods: In this study, we employed translatome profiling of paclitaxel-treated cancer cells, live-cell imaging analysis, gene knockdown/knockout, and in vitro cancer-macrophage coculture assays to unravel a novel chemoresistance mechanism mediated by tumor-macrophage interaction via the NOTCH2-JAG1 axis. The in vitro data were further validated by multiple xenograft, syngeneic and patient-derived xenograft mouse tumor models of ovarian cancer as well as ovarian cancer patient samples.

Results: We found paclitaxel selectively induced translational upregulation of NOTCH2 via cytoplasmic polyadenylation, and this NOTCH2 upregulation persisted after mitotic exit. Subsequent NOTCH2 activation by JAG1 expressed mainly on the neighboring macrophages promoted tumor cell survival and simulated cytokine release, such as CSF1 and IL-1β, that recruited JAG1-expressing macrophages, thus forming a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. Genetic depletion or pharmacological inhibition of NOTCH2 with the γ-secretase inhibitor attenuated macrophage infiltration and sensitized tumor response to paclitaxel in multiple preclinical models of ovarian cancer. Moreover, single-cell RNA sequencing analysis identified a JAG1-high macrophage subset that was enriched by paclitaxel treatment and attenuated by NOTCH inhibition. Clinically, high NOTCH2 expression in ovarian tumors was associated with recurrence and shorter progression-free survival of ovarian cancer patients.

Conclusions: Paclitaxel-induced translational upregulation of NOTCH2 enables immediate juxtacrine activation by JAG1-positive macrophages, coupling tumor cell survival with immune remodeling in the tumor microenvironment to drive chemoresistance. Our results suggest NOTCH2 is a viable biomarker for paclitaxel resistance and that combining NOTCH2 inhibitor with taxane is an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.

Keywords: Anti-mitotic drugs; Chemoresistance; NOTCH2 signaling; Paclitaxel; Translational regulation; Tumor-macrophage interaction.

Abstract

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