FBXW5 blunts RIGI/MDA5-IFN signaling to drive immunoevasion and chemo-immune resistance in triple-negative breast cancer models

Xin Li; Tong Chen; Wenjing Zhao; Jiaxing Li; Yifan Shang; Bing Chen; Lijuan Wang; Ning Zhang; Xiaoli Kong; Yiran Liang; Yaming Li; Chen Li; Dianwen Han; Xi Chen; Shan Jiang; Chao Yang; Dan Luo; Tingting Ma; Qifeng Yang

doi:10.1172/JCI201573

¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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¹Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, China

²Biological Resource Center, Qilu Hospital of Shandong University, Jinan, China

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J Clin Invest. https://doi.org/10.1172/JCI201573.
Copyright © 2026, Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published August 25, 2026 - Version history

Triple-negative breast cancer (TNBC), characterized by aggressive behavior and poor prognosis, presents a formidable clinical challenge. Despite guideline endorsement of chemoimmunotherapy as a standard treatment in TNBC, durable responses remain rare, largely due to an immunologically “cold” tumor microenvironment (TME). Through integrated analysis, we identified the F-box protein FBXW5 as a tumor-intrinsic immunosuppressive regulator, whose expression is elevated in immunologically “cold” TNBC and correlates with dismal patient survival. Genetic knockdown of murine Fbxw5 suppressed tumor growth, reinvigorated CD8+ T cell-mediated antitumor immunity, and sensitized TNBC tumors to both single-agent and combined chemo-immune therapy in preclinical models. Mechanistically, FBXW5 acts within the SKP1/CUL1/F-box protein (SCF) E3 ligase complex to bind RIGI and MDA5, promoting their K27-linked polyubiquitination and subsequent SQSTM1-mediated autophagic degradation. This process blunts cytosolic RNA sensing and type I interferon (IFN-I) signaling, thereby limiting CD8+ T cell infiltration and activation. Our findings establish FBXW5 as a master regulator of the “cold” TME, presenting a potential predictive biomarker and actionable therapeutic target for enhancing chemoimmunotherapy in TNBC.

Version 1 (August 25, 2026): In-Press Preview

FBXW5 blunts RIGI/MDA5-IFN signaling to drive immunoevasion and chemo-immune resistance in triple-negative breast cancer models

Xin Li,¹ Tong Chen,¹ Wenjing Zhao,² Jiaxing Li,¹ Yifan Shang,¹ Bing Chen,² Lijuan Wang,² Ning Zhang,¹ Xiaoli Kong,¹ Yiran Liang,¹ Yaming Li,¹ Chen Li,¹ Dianwen Han,¹ Xi Chen,¹ Shan Jiang,¹ Chao Yang,¹ Dan Luo,¹ Tingting Ma,¹ and Qifeng Yang¹

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FBXW5 blunts RIGI/MDA5-IFN signaling to drive immunoevasion and chemo-immune resistance in triple-negative breast cancer models

Xin Li,1 Tong Chen,1 Wenjing Zhao,2 Jiaxing Li,1 Yifan Shang,1 Bing Chen,2 Lijuan Wang,2 Ning Zhang,1 Xiaoli Kong,1 Yiran Liang,1 Yaming Li,1 Chen Li,1 Dianwen Han,1 Xi Chen,1 Shan Jiang,1 Chao Yang,1 Dan Luo,1 Tingting Ma,1 and Qifeng Yang1

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Xin Li,¹ Tong Chen,¹ Wenjing Zhao,² Jiaxing Li,¹ Yifan Shang,¹ Bing Chen,² Lijuan Wang,² Ning Zhang,¹ Xiaoli Kong,¹ Yiran Liang,¹ Yaming Li,¹ Chen Li,¹ Dianwen Han,¹ Xi Chen,¹ Shan Jiang,¹ Chao Yang,¹ Dan Luo,¹ Tingting Ma,¹ and Qifeng Yang¹