Sarcomas are a rare and heterogeneous group of malignant tumors that pose significant clinical challenges, including delayed diagnosis, therapeutic resistance, and lack of reliable biomarkers. Despite advances in surgery and chemotherapy, effective treatment options for advanced disease remain limited, underscoring the urgent need to identify novel therapeutic vulnerabilities. The unfolded protein response (UPR), a conserved cellular stress pathway that maintains proteostasis under conditions of endoplasmic reticulum stress, has emerged as a critical modulator of cancer cell fate. By regulating protein folding, redox balance, and survival pathways, the UPR exerts a dual role in tumor biology, supporting tumor growth under stress while triggering apoptosis when stress becomes sustained or severe. In sarcomas, accumulating evidence indicates that UPR activation contributes to metabolic adaptation, angiogenesis, immune evasion, and chemoresistance. Drawing on the current literature encompassing preclinical models, recent translational research (PubMed from 2000 to 2025), and registered clinical trials, this narrative review synthesizes current knowledge on the multifaceted role of the UPR in sarcoma pathogenesis, with a particular focus on osteosarcoma. Furthermore, it explores the feasibility of UPR-targeted strategies as adjuvant or combinatorial approaches. In conclusion, this review provides an integrated and in-depth analysis of UPR-mediated mechanisms in sarcomas, offering perspectives on how targeting this pathway could accelerate the development of more effective and personalized treatments.
肉瘤是一类罕见且异质性的恶性肿瘤，其临床诊疗面临多重挑战，包括诊断延迟、治疗抵抗及缺乏可靠的生物标志物。尽管手术和化疗技术有所进展，晚期肉瘤的有效治疗方案仍十分有限，这凸显了探索新型治疗靶点的迫切需求。未折叠蛋白反应作为一种保守的细胞应激通路，在内质网应激状态下维持蛋白质稳态，现已成为调控癌细胞命运的关键枢纽。该通路通过调节蛋白质折叠、氧化还原平衡及生存信号途径，在肿瘤生物学中发挥双重作用：既能在应激条件下支持肿瘤生长，又能在持续或严重应激时触发细胞凋亡。在肉瘤研究中，越来越多的证据表明未折叠蛋白反应的激活参与代谢适应、血管生成、免疫逃逸和化疗抵抗等过程。本文基于涵盖临床前模型、近期转化研究（2000-2025年PubMed数据库）及已注册临床试验的现有文献，系统综述了未折叠蛋白反应在肉瘤发病机制中的多维度作用，特别聚焦于骨肉瘤的研究进展。此外，本文探讨了以未折叠蛋白反应为靶点的辅助或联合治疗策略的可行性。综上所述，本综述对未折叠蛋白反应在肉瘤中的调控机制进行了整合性深入分析，为通过靶向该通路开发更有效、个性化的治疗方案提供了前瞻性视角。
The Unfolded Protein Response in Sarcomas: From Proteostasis to Therapy Resistance
肿瘤(癌症)患者之家