FBXW5 blunts RIGI/MDA5/IFN signaling to drive immune evasion 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
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
View: Text | PDF
Research Article Cell biology Immunology Oncology

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

Abstract

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 chemoimmunotherapy in preclinical models. Mechanistically, FBXW5 acts within the SKP1/CUL1/F-box protein 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 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.

Authors

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

×

Figure 2

FBXW5 suppresses CD8+ T cell infiltration and activation via inhibition of type I IFN signaling in TNBC.

Options: View larger image (or click on image) Download as PowerPoint
FBXW5 suppresses CD8+ T cell infiltration and activation via inhibition ...
(A–C) CyTOF profiling of control (NC) and murine Fbxw5-knockdown tumors: schematic workflow (A), t-SNE projections identifying 17 major immune clusters (B), and frequency quantification of cell populations (C). sh, shRNA. (D and E) Subcutaneous 4T1 tumor growth in immunocompetent BALB/c versus T cell–deficient nude mice, including schematics (D), representative images (E), and growth curves (F). (G and H) Flow cytometric quantification of tumor-infiltrating CD8+ T cells (G) and effector subsets (IFN-γ+ or GZMB+) in BALB/c mice (H). (I) Schematic of human CD8+ T cells treated with MDA-MB-468–conditioned medium and corresponding migration rates. (J–L) Schematic of human CD8+ T cell and MDA-MB-468 cell direct coculture model (J), flow cytometric analysis of apoptosis levels of tumor cells (K), and IFN-γ and TNF-α in CFSE-labeled CD8+ T cells (L) after 48 hours’ coculture. (M) GO enrichment of DEGs and heatmap depicting downregulated type I IFN signaling genes (ISGs) in Fbxw5-overexpressing versus control 4T1 cells. (N and O) In vivo rescue assays in BALB/c mice: tumor images and growth curves (N), with flow cytometric quantification of total CD8+ T cells (O). Statistical significance: unpaired 2-tailed Welch’s t test (C and G–L); 2-way ANOVA with Šídák’s post hoc test (F, N, and O). Group comparisons: black (A vs. B), green (A vs. C), red (B vs. D) in N. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.