PO.PR01.04 · 预防研究
通过靶向腺苷信号传导提高肥胖乳腺癌的治疗疗效
Improving therapeutic efficacy by targeting adenosine signaling in obese breast cancers
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摘要 Abstract
中文摘要
肥胖癌症患者中积累的脂肪细胞显著削弱治疗疗效，然而其潜在机制在很大程度上仍未明确。在此，我们鉴定出一条OTUD4驱动的蛋白水解轴，是肥胖相关三阴性乳腺癌（TNBC）免疫抑制的关键调控因子。OTUD4的过度激活与TGF-beta协同增强CD73介导的腺苷能信号传导，建立起一个富含TREM2+ APOE+载脂肿瘤相关巨噬细胞（LL-TAMs）的免疫抑制性肿瘤微环境（TME）。这一富含腺苷的微环境促进LL-TAM向CCL2+ IL6+胞葬表型极化，共同抑制细胞毒性T细胞活性。空间和组织学分析揭示了TGF-beta、OTUD4和CD73在免疫抑制肿瘤区域内的区域性共表达，其空间上与LL-TAM簇一致。为了在治疗上靶向该通路，我们开发了W-DB53，一种选择性小分子抑制剂，可破坏OTUD4-CD73相互作用、耗竭LL-TAMs、恢复T细胞浸润，并在肥胖TNBC模型中与免疫检查点抑制剂（ICIs）协同作用。这些发现确立了W-DB53作为一种巨噬细胞重塑性蛋白-蛋白相互作用（PPI）抑制剂，可重编程胞葬作用并克服TNBC中肥胖驱动的免疫抵抗。
查看英文原文 English abstract
Accumulated adipocytes in obese cancer patients significantly compromise therapeutic efficacy,yet the underlying mechanisms remain largely undefined. Here, we identify an OTUD4-driven proteolyticaxis as a critical regulator of immune suppression in obesity-associated triple-negative breast cancer(TNBC). Hyperactivation of OTUD4 enhances CD73-mediated adenosinergic signaling in cooperationwith TGF-beta, establishing an immunosuppressive tumor microenvironment (TME) enriched with TREM2 + APOE + lipid-laden tumor-associated macrophages (LL-TAMs). This adenosine-rich niche promotes LL-TAM polarization toward a CCL2 + IL6 + efferocytic phenotype, collectively dampening cytotoxic T-cellactivity. Spatial and histologic analyses reveal regional co-expression of TGF-beta, OTUD4, and CD73 withinimmune-suppressed tumor zones that spatially align with LL-TAM clusters. To therapeutically target thispathway, we developed W-DB53, a selective small-molecule inhibitor that disrupts the OTUD4-CD73interaction, depletes LL-TAMs, restores T-cell infiltration, and synergizes with immune checkpointinhibitors (ICIs) in obese TNBC models. These findings establish W-DB53 as a macrophage-remodelingprotein-protein interaction (PPI) inhibitor that reprograms efferocytosis and overcomes obesity-drivenimmune resistance in TNBC.
利益披露 Disclosure
Y. Zhu, None..
A. Uddin, None..
X. Cui, None..
Y. Wan, None.