Mitochondrial metabolic reprogramming-mediated immunogenic cell death reveals immune and prognostic features of clear cell renal cell carcinoma
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Updated: Jul 29, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Lin Yang1, Jing Xiong1, Sheng Li1
1Department of Urology, First Affiliated Hospital of Nanchang University, Nanchang, China.
Background:
Mitochondrial metabolic reprogramming (MMR)-mediated immunogenic cell death (ICD) is closely related to the tumor microenvironment (TME). Our purpose was to reveal the TME characteristics of clear cell renal cell carcinoma (ccRCC) by using them.
Methods:
Target genes were obtained by intersecting ccRCC differentially expressed genes (DEGs, tumor VS normal) with MMR and ICD-related genes. For the risk model, univariate COX regression and K-M survival analysis were used to identify genes most associated with overall survival (OS). Differences in the TME, function, tumor mutational load (TMB), and microsatellite instability (MSI) between high and low-risk groups were subsequently compared. Using risk scores and clinical variables, a nomogram was constructed. Predictive performance was evaluated by calibration plots and receiver operating characteristics (ROC).
Results:
We screened 140 DEGs, including 12 prognostic genes for the construction of risk models. We found that the immune score, immune cell infiltration abundance, and TMB and MSI scores were higher in the high-risk group. Thus, high-risk populations would benefit more from immunotherapy. We also identified the three genes (CENPA, TIMP1, and MYCN) as potential therapeutic targets, of which MYCN is a novel biomarker. Additionally, the nomogram performed well in both TCGA (1-year AUC=0.862) and E-MTAB-1980 cohorts (1-year AUC=0.909).
Conclusions:
Our model and nomogram allow accurate prediction of patients' prognoses and immunotherapy responses.
Insights
This study reveals clear cell renal cell carcinoma (ccRCC) tumor microenvironment (TME) characteristics linked to mitochondrial metabolic reprogramming (MMR) and immunogenic cell death (ICD). A novel nomogram accurately predicts ccRCC patient prognosis and immunotherapy response.
Area of Science:
- Oncology
- Immunology
- Metabolism
Background:
- Mitochondrial metabolic reprogramming (MMR) and immunogenic cell death (ICD) are critical factors influencing the tumor microenvironment (TME).
- Understanding the interplay of MMR and ICD within the TME is essential for advancing clear cell renal cell carcinoma (ccRCC) research.
Purpose of the Study:
- To characterize the TME of ccRCC by analyzing MMR- and ICD-related genes.
- To develop a predictive model for patient prognosis and immunotherapy response in ccRCC.
Main Methods:
- Differential gene expression analysis identified ccRCC-specific genes.
- Univariate COX regression and Kaplan-Meier survival analysis selected prognostic genes for a risk model.
- Comparison of TME features, tumor mutational load (TMB), and microsatellite instability (MSI) between high- and low-risk groups.
- Construction and validation of a nomogram for predicting patient outcomes.
Main Results:
- A risk model was built using 12 prognostic genes from 140 differentially expressed genes (DEGs).
- High-risk ccRCC patients exhibited elevated immune scores, immune cell infiltration, TMB, and MSI.
- Genes including *CENPA*, *TIMP1*, and *MYCN* were identified as potential therapeutic targets, with *MYCN* noted as a novel biomarker.
- The nomogram demonstrated strong predictive performance in both TCGA and E-MTAB-1980 cohorts.
Conclusions:
- The developed risk model and nomogram offer accurate prediction of ccRCC patient prognoses.
- The findings suggest that high-risk ccRCC populations may benefit significantly from immunotherapy.
- The study provides valuable tools for personalized treatment strategies in ccRCC.
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