ArticleThe Journal of clinical investigation2026
FBXW5 blunts RIGI/MDA5/IFN signaling to drive immune evasion and chemo-immune resistance in triple-negative breast cancer models.
Article in The Journal of clinical investigation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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.
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