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Comprehensive Profiling Reveals Prognostic and Immunogenic Characteristics of Necroptosis in Soft Tissue Sarcomas
Lin Qi1,2, Ruiling Xu1,2, Xiaolei Ren1,2
1Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Soft tissue sarcomas (STSs) are heterogeneous malignancies derived from mesenchymal cells. Due to its rarity, heterogeneity, and limited overall response to chemotherapy, STSs represent a therapeutic challenge. Necroptosis is a novel therapeutic strategy for enhancing immunotherapy of cancer. Nevertheless, no research has explored the relationship between necroptosis-related genes (NRGs) and STSs. In this study, differentially expressed NRGs were identified using The Cancer Genome Atlas (TCGA) and The Cancer Genotype-Tissue Expression (GTEx) project. The expression levels of 34 NRGs were significantly different. Several key NRGs were validated using RT-qPCR and our own sequencing data. Patients with STSs were divided into two clusters using consensus cluster analysis, and significant differences were observed in their survival (p=0.002). We found the differentially expressed genes (DEGs) between the two clusters and carried out subsequent analysis. The necroptosis-related gene signatures with 10 key DEGs were identified with a risk score constructed. The prognosis of TCGA-SARC cohort with low necroptosis-related risk score was better (p<0.001). Meanwhile, the low-risk group had a significantly increased immune infiltration. Using the data of GSE17118 and another immunotherapy cohort as external validations, we observed significant survival differences between the two risk groups (p=0.019). The necroptosis-related risk score proved to be an independent prognostic factor, and a nomogram was further established and integrated with other clinical features. Notably, the necroptosis-related gene signature could also act as the prognostic indicator in other malignancies based on pan-cancer analysis. In summary, the study outlines NRGs in STSs and their potential role in prognosis and will be one of the important directions for future research.
Insights
This study identifies necroptosis-related genes (NRGs) as potential biomarkers for soft tissue sarcomas (STSs). A novel NRG-based risk score effectively predicts patient prognosis and immune infiltration in STSs.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Soft tissue sarcomas (STSs) are rare, heterogeneous cancers posing significant therapeutic challenges.
- Limited chemotherapy response and rarity necessitate novel treatment strategies.
- Necroptosis, a regulated cell death pathway, is emerging as a key factor in cancer immunotherapy.
Purpose of the Study:
- To investigate the role of necroptosis-related genes (NRGs) in soft tissue sarcomas (STSs).
- To identify NRGs that can serve as prognostic biomarkers for STSs.
- To explore the relationship between NRGs, prognosis, and immune infiltration in STSs.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects to identify differentially expressed NRGs.
- Employed consensus cluster analysis to stratify STS patients into prognostic groups.
- Developed a 10-gene necroptosis-related risk score and validated it using external datasets and a nomogram.
Main Results:
- Identified significant differences in 34 NRGs between STS and normal tissues.
- Established two distinct STS clusters with significant survival differences (p=0.002).
- The 10-gene necroptosis-related risk score accurately predicted prognosis (p<0.001) and correlated with increased immune infiltration in TCGA-SARC cohort.
Conclusions:
- Necroptosis-related gene signatures are crucial prognostic indicators for STSs.
- The developed risk score demonstrates potential for predicting STS patient outcomes and guiding immunotherapy.
- Necroptosis-related genes may serve as prognostic markers across various cancer types, warranting further investigation.

