WDR82 suppresses breast cancer progression by inhibiting ERK-driven chemokine expression and neutrophil infiltration

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Abstract
Elucidating tumor-intrinsic mechanisms orchestrating immunosuppressive tumor microenvironment (TME) and cancer immunoevasion is essential for overcoming cancer immunotherapy resistance and developing novel therapeutic strategies. WDR82, a member of the WD-40 protein family, exhibits context-dependent regulation of cancer with undefined role in breast cancer and immunosuppressive TME. Here we identify WDR82 as a critical tumor suppressor governing immune surveillance by restraining the ERK-chemokine-neutrophil axis. WDR82 expression is downregulated in human breast cancer and correlates with poor prognosis. Although WDR82 promotes tumor cell proliferation in vitro, it suppresses tumor growth in vivo exclusively in immunocompetent hosts by enhancing neutrophil infiltration and CD8⁺ T cell exhaustion, creating an immunosuppressive TME. Neutrophil depletion abolishes WDR82's tumor-suppressive effect, confirming the functional dependency on this axis. Mechanistically, WDR82 directly binds MEK1/2 to disassemble c-RAF-MEK binding and inactivate ERK signaling. Wdr82 deletion restores ERK-dependent tumor cell CXCL2 and CXCL7 production to promote CXCR2-mediated neutrophil recruitment in the TME. Importantly, intratumoral WDR82-expressing adenovirus delivery reverses neutrophil accumulation and T cell exhaustion, suppressing tumor progression. Our findings uncover a previously unrecognized mechanism by which WDR82 suppresses MEK-ERK signaling, ERK-dependent chemokines production and neutrophil infiltration, consequently relieving immunosuppressive TME. This work establishes a promising therapeutic strategy for breast cancer.

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