Soft tissue and bone sarcomas are malignancies of mesenchymal origin, and more than 50 subtypes are defined. For most sarcomas, locally advanced or unresectable disease is still treated with cytotoxic chemotherapy. Recently, our understanding of subtype-specific cancer biology has expanded, and it has revealed distinct molecular alterations responsible for tumor initiation and progression. These findings have motivated the development of targeted therapies that are being evaluated in subtype-specific or biomarker-driven clinical trials. Indeed, the spectrum of targeted drug development in sarcoma now spans many of the most active paradigms in cancer research and includes agents that target cancer-related vulnerabilities in receptor tyrosine kinases and intracellular signaling pathways, epigenetics, metabolism, nuclear-cytoplasmic transport, and many others. Our understanding of the sarcoma immune microenvironment and heterogeneous mechanisms of tumor immune evasion has also expanded. Although a subset of sarcomas appears inflamed and responsive to immune checkpoint blockade with programmed death 1 (PD-1) targeted agents, novel immunotherapies and combinations likely will be needed for most subtypes. A variety of approaches-including targeting immune checkpoints other than PD-1; modulating tumor-associated macrophage phenotype from tumor-promoting to tumor-suppressive status; using cellular-based therapies, such as chimeric antigen and high-affinity T-cell receptors to deepen the adaptive immune response; and reinvigorating older approaches, such as vaccines and oncolytic virus-based treatments-are being investigated. The goal of these new approaches is to harness subtype-specific insights into cancer and immune biology to bring more effective and less toxic treatments to the clinic for the benefit of patients with sarcoma.

中文翻译：

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肉瘤中新兴的靶向和免疫疗法

软组织肉瘤和骨肉瘤是间充质来源的恶性肿瘤，定义了 50 多种亚型。对于大多数肉瘤，局部晚期或不可切除的疾病仍然用细胞毒性化学疗法治疗。最近，我们对亚型特异性癌症生物学的理解有所扩展，它揭示了导致肿瘤发生和进展的不同分子改变。这些发现推动了靶向疗法的开发，这些疗法正在亚型特异性或生物标志物驱动的临床试验中进行评估。事实上，肉瘤靶向药物开发的范围现在跨越了癌症研究中许多最活跃的范式，包括针对受体酪氨酸激酶和细胞内信号通路、表观遗传学、代谢、核-细胞质转运、和许多其他人。我们对肉瘤免疫微环境和肿瘤免疫逃避异质机制的理解也得到了扩展。尽管一部分肉瘤出现炎症并且对程序性死亡 1 (PD-1) 靶向药物的免疫检查点阻断有反应，但大多数亚型可能需要新的免疫疗法和组合。多种方法——包括靶向PD-1以外的免疫检查点；调节肿瘤相关巨噬细胞表型从肿瘤促进状态到肿瘤抑制状态；使用基于细胞的疗法，例如嵌合抗原和高亲和力 T 细胞受体来加深适应性免疫反应；正在研究重振旧方法，例如疫苗和基于溶瘤病毒的治疗。