Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy.
恶性外周神经鞘瘤（MPNSTs）是一种致命的软组织肉瘤亚型，目前缺乏有效的治疗手段。当前，MPNSTs的最佳治疗方式为广泛阴性切缘的完全手术切除，但常因肿瘤体积、位置和/或转移灶的存在而难以实现。放疗或化疗可与手术联合应用，但患者反应普遍不佳。靶向治疗——包括针对致癌蛋白（如丝裂原活化蛋白激酶激酶（MEK）、细胞周期蛋白依赖性激酶4和6（CDK4/6）以及含Src同源2结构域的蛋白酪氨酸磷酸酶2（SHP2））的小分子抑制剂——是极具前景的MPNSTs治疗策略，尤其当联合使用时，但此类疗法尚未获批。免疫治疗方法在其他某些癌症治疗中取得了革命性进展，但其作为单药在肉瘤治疗中的应用有限，且未获准用于MPNSTs。MPNSTs的免疫抑制微环境被认为赋予其固有的治疗抵抗性，尤其对免疫疗法。将固有的“冷”肿瘤微环境重塑为“热”免疫环境以增强免疫疗法的抗肿瘤活性，已成为整个癌症研究领域高度关注的焦点。本综述重点关注靶向MPNSTs失调因子及通路的新型疗法，以及目前针对该疾病正在研究的不同类型免疫疗法。同时，我们还探讨了如何联合特定疗法以重塑MPNSTs免疫微环境，从而对免疫疗法产生持久的抗肿瘤免疫应答。
肿瘤(癌症)患者之家