GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325774/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325774GEOGSEfalseWDR82 suppresses breast cancer progression by inhibiting ERK-driven chemokine expression and neutrophil infiltrationElucidating tumor-intrinsic mechanisms that drive immune evasion and shape an immunosuppressive tumor microenvironment (TME) is essential for overcoming resistance to cancer immunotherapy and developing novel therapeutic strategies. WDR82, a member of the WD-40 protein family, exhibits context-dependent regulation of cancer, yet its role in breast cancer and its influence on the immunosuppressive TME remain undefined. Here we identify WDR82 as a critical tumor suppressor that governs immune surveillance by restraining the ERK–chemokine–neutrophil axis. WDR82 expression is downregulated in human breast cancer and correlates with poor prognosis.Using orthotopic models, we uncover a functional paradox: while Wdr82 deficiency suppresses tumor cell proliferation in vitro, it accelerates tumor growth in vivo exclusively in immunocompetent hosts, driving enhanced neutrophil infiltration and CD8⁺ T cell exhaustion. Mechanistically, WDR82 directly binds MEK1/2, disrupting c-RAF-MEK assembly and restraining ERK activation. Loss of Wdr82 relieves this inhibition, driving ERK-dependent production of CXCL2 and CXCL7, the key neutrophil chemoattractants that promote CXCR2-mediated recruitment. Neutrophil depletion abolishes the tumor-promoting effect of Wdr82 deficiency, confirming the functional dependency on this axis. Importantly, intratumoral delivery of WDR82-expressing adenovirus reverses neutrophil accumulation, alleviates T cell exhaustion, and suppresses tumor progression. Our findings uncover a previously unrecognized mechanism by which WDR82 links tumor-intrinsic signaling to TME remodeling, establishing a promising therapeutic strategy for breast cancer through targeting the ERK–chemokine–neutrophil axis.2026/06/25GSE325774GSM9613183GSM9613184GSM9613185GSM9613186GSM9613180GSM9613181GSM9613182GSM9613178GSM961317917021325774Mus musculus[42328439]