Malignant peripheral nerve sheath tumor (MPNST) is a rare but aggressive soft-tissue sarcoma characterized by poor response to therapy. The primary treatment remains surgical resection with negative margins. Nonetheless, in the setting of neurofibromatosis type 1 (NF1), the five-year survival rate is at 20–50%, with recurrence occurring in up to 50% of individuals. For patients with metastatic and unresectable disease, current treatment options include cytotoxic chemotherapy, which offers minimal benefit, and most patients die within five years of diagnosis. Despite advances in targeted therapy focusing on inhibiting Ras signaling and its downstream effectors, clinical trials report minimal clinical benefit, highlighting the need to explore alternative pathways in MPNST pathogenesis. Here, we discuss the role of the E3 ubiquitin ligase, UBR5, in cancer progression and immune modulation across various malignancies, including breast, lung, and ovarian cancer. We focus on mechanisms by which UBR5 contributes to tumorigenesis, focusing on its influence on tumor microenvironment and immune modulation. Additionally, we explore UBR5’s roles in normal tissue function, DNA damage response, metastasis, and therapeutic resistance, illustrating its multifaceted contribution to cancer biology. We discuss evidence implicating UBR5 in immune evasion and highlight its potential as a therapeutic target to enhance the efficacy of immune checkpoint blockade (ICB) therapy in MPNST, a tumor typically characterized by an immune cold microenvironment. We outline current immune-based strategies and challenges in MPNST management, ongoing efforts to shift the immune landscape in MPNST, and ultimately, we suggest that targeting UBR5 could be a novel strategy to potentiate ICB therapy-mediated anti-tumor immune response and clinical outcomes, particularly in MPNST patients with inoperable or metastatic disease.
恶性外周神经鞘瘤（MPNST）是一种罕见但侵袭性强的软组织肉瘤，其特点是对治疗反应不佳。主要治疗手段仍为手术切除并确保切缘阴性。然而，在1型神经纤维瘤病（NF1）背景下，患者五年生存率仅为20%至50%，且高达50%的个体会出现复发。对于转移性和不可切除的病例，当前治疗方案包括细胞毒性化疗，但其获益有限，大多数患者在确诊后五年内死亡。尽管针对抑制Ras信号通路及其下游效应器的靶向治疗已取得进展，但临床试验报告显示其临床获益甚微，这凸显了探索MPNST发病机制中替代通路的重要性。本文探讨了E3泛素连接酶UBR5在多种恶性肿瘤（包括乳腺癌、肺癌和卵巢癌）的癌症进展和免疫调节中的作用。我们重点关注UBR5促进肿瘤发生的机制，特别是其对肿瘤微环境和免疫调节的影响。此外，我们探讨了UBR5在正常组织功能、DNA损伤应答、转移和治疗抵抗中的作用，阐明其在癌症生物学中的多面性贡献。我们讨论了UBR5参与免疫逃逸的证据，并强调其作为治疗靶点的潜力，以增强免疫检查点阻断（ICB）疗法在MPNST中的疗效——该肿瘤通常以免疫冷微环境为特征。我们概述了当前MPNST管理中基于免疫的策略及面临的挑战，以及改变MPNST免疫微环境的持续努力。最后，我们认为靶向UBR5可能成为一种新策略，可增强ICB疗法介导的抗肿瘤免疫反应并改善临床结局，尤其对于无法手术或转移性MPNST患者。
肿瘤(癌症)患者之家