恶性间皮瘤（MM）是一种罕见的肿瘤，预后不佳。当前治疗方法效果低下，强调需要确定更有效的治疗方法，旨在改善MM患者的生存率。博来佐米布（Bor）是20S核心蛋白酶体中胰蛋白酶样活性的特异性可逆抑制剂，目前已获批用于多发性骨髓瘤和曼特尔细胞淋巴瘤的治疗。然而，由于其静脉注射后对实体肿瘤组织的渗透性和积累性较低，Bor在实体肿瘤中的临床效果受到限制。这些局限性可以通过腔内给药来克服，在增加局部药物浓度和降低系统毒性的优势下。在本研究中，我们研究了Bor对不同组织类型的人类MM细胞系在体内培养中的细胞存活、细胞周期分布以及凋亡和促存活通路的调节作用。此外，使用小鼠MM细胞系，在同基因C57BL/6小鼠腹腔内注射后能够产生腹水的模型中，我们研究了体内腹腔注射Bor对肿瘤生长和肿瘤免疫微环境调节的影响。我们证明了Bor抑制了MM细胞的生长并诱导了细胞凋亡。此外，Bor激活了蛋白质错构反应，然而这似乎参与了降低细胞对药物细胞毒作用的敏感性。Bor还影响了EGFR和ErbB2的表达以及下游的促存活信号效应子，包括ERK1/2和AKT的活化。在体内，Bor能够抑制MM生长并延长小鼠的生存期。Bor介导的肿瘤进展延迟是由被招募到肿瘤微环境中的T淋巴细胞的活化增加所维持的。本文介绍的结果支持在MM中使用Bor，并倡导未来的研究以确定Bor和基于Bor的联合方案对这种难治性的侵袭性肿瘤的治疗潜力。 © 2023. 作者（们）。

Malignant mesothelioma (MM) is a rare tumor with a dismal prognosis. The low efficacy of current treatment options highlights the urge to identify more effective therapies aimed at improving MM patients' survival. Bortezomib (Bor) is a specific and reversible inhibitor of the chymotrypsin-like activity of the 20S core of the proteasome, currently approved for the treatment of multiple myeloma and mantle cell lymphoma. On the other hand, Bor appears to have limited clinical effects on solid tumors, because of its low penetration and accumulation into tumor tissues following intravenous administration. These limitations could be overcome in MM through intracavitary delivery, with the advantage of increasing local drug concentration and decreasing systemic toxicity.In this study, we investigated the effects of Bor on cell survival, cell cycle distribution and modulation of apoptotic and pro-survival pathways in human MM cell lines of different histotypes cultured in vitro. Further, using a mouse MM cell line that reproducibly forms ascites when intraperitoneally injected in syngeneic C57BL/6 mice, we investigated the effects of intraperitoneal Bor administration in vivo on both tumor growth and the modulation of the tumor immune microenvironment.We demonstrate that Bor inhibited MM cell growth and induced apoptosis. Further, Bor activated the Unfolded Protein Response, which however appeared to participate in lowering cells' sensitivity to the drug's cytotoxic effects. Bor also affected the expression of EGFR and ErbB2 and the activation of downstream pro-survival signaling effectors, including ERK1/2 and AKT. In vivo, Bor was able to suppress MM growth and extend mice survival. The Bor-mediated delay of tumor progression was sustained by increased activation of T lymphocytes recruited to the tumor microenvironment.The results presented herein support the use of Bor in MM and advocate future studies aimed at defining the therapeutic potential of Bor and Bor-based combination regimens for this treatment-resistant, aggressive tumor.© 2023. The Author(s).