TGF-β signaling is a key player in tumor progression and immune evasion, and is associated with poor response to cancer immunotherapies. Here, we identified ubiquitin-specific peptidase 8 (USP8) as a metastasis enhancer and a highly active deubiquitinase in aggressive breast tumors. USP8 acts both as a cancer stemness-promoting factor and an activator of the TGF-β/SMAD signaling pathway. USP8 directly deubiquitinates and stabilizes the type II TGF-β receptor TβRII, leading to its increased expression in the plasma membrane and in tumor-derived extracellular vesicles (TEVs). Increased USP8 activity was observed in patients resistant to neoadjuvant chemotherapies. USP8 promotes TGF-β/SMAD-induced epithelial-mesenchymal transition (EMT), invasion, and metastasis in tumor cells. USP8 expression also enables TβRII+ circulating extracellular vesicles (crEVs) to induce T cell exhaustion and chemoimmunotherapy resistance. Pharmacological inhibition of USP8 antagonizes TGF-β/SMAD signaling, and reduces TβRII stability and the number of TβRII+ crEVs to prevent CD8+ T cell exhaustion and to reactivate anti-tumor immunity. Our findings not only reveal a novel mechanism whereby USP8 regulates the cancer microenvironment but also demonstrate the therapeutic advantages of engineering USP8 inhibitors to simultaneously suppress metastasis and improve the efficacy of cancer immunotherapy.

中文翻译：

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USP8 通过去泛素化 TGF-β 受体 TβRII 促进癌症进展和细胞外囊泡介导的 CD8+ T 细胞耗竭

TGF-β信号传导在肿瘤进展和免疫逃避中发挥着关键作用，并且与癌症免疫疗法的不良反应有关。在这里，我们鉴定出泛素特异性肽酶 8 (USP8) 作为侵袭性乳腺肿瘤中的转移增强剂和高活性去泛素酶。USP8 既可作为癌症干细胞促进因子，又可作为 TGF-β/SMAD 信号通路的激活剂。USP8 直接去泛素化并稳定 II 型 TGF-β 受体 TβRII，导致其在质膜和肿瘤源性细胞外囊泡 (TEV) 中的表达增加。在对新辅助化疗耐药的患者中观察到 USP8 活性增加。USP8 促进 TGF-β/SMAD 诱导的肿瘤细胞上皮间质转化 (EMT)、侵袭和转移。USP8 表达还使 TβRII+ 循环细胞外囊泡 (crEV) 能够诱导 T 细胞耗竭和化学免疫治疗耐药。USP8 的药理抑制可拮抗 TGF-β/SMAD 信号传导，并降低 TβRII 稳定性和 TβRII+ crEV 数量，以防止 CD8+ T 细胞耗竭并重新激活抗肿瘤免疫。我们的研究结果不仅揭示了USP8调节癌症微环境的新机制，而且还证明了工程化USP8抑制剂在抑制转移和提高癌症免疫治疗疗效方面的治疗优势。并降低 TβRII 稳定性和 TβRII+ crEV 数量，以防止 CD8+ T 细胞耗竭并重新激活抗肿瘤免疫。我们的研究结果不仅揭示了USP8调节癌症微环境的新机制，而且还证明了工程化USP8抑制剂在抑制转移和提高癌症免疫治疗疗效方面的治疗优势。并降低 TβRII 稳定性和 TβRII+ crEV 数量，以防止 CD8+ T 细胞耗竭并重新激活抗肿瘤免疫。我们的研究结果不仅揭示了USP8调节癌症微环境的新机制，而且还证明了工程化USP8抑制剂在抑制转移和提高癌症免疫治疗疗效方面的治疗优势。