The Unfolded Protein Response in Sarcomas: From Proteostasis to Therapy Resistance

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.