NME4: A novel metabolic-associated biomarker for prognosis prediction and immunotherapy response evaluation in clear cell renal cell carcinoma

Shilong Cheng; Qisheng Lin; Kai Chen; Jiaxing Wang; Hangyang Peng; Yaqiang Huang; Xiangming Mao; Jianming Lu; Chuanfan Zhong

doi:10.1016/j.molimm.2025.06.011

NME4: A novel metabolic-associated biomarker for prognosis prediction and immunotherapy response evaluation in clear cell renal cell carcinoma

Mol Immunol. 2025 Jul 1:184:149-163. doi: 10.1016/j.molimm.2025.06.011. Online ahead of print.

Authors

Shilong Cheng¹, Qisheng Lin², Kai Chen³, Jiaxing Wang¹, Hangyang Peng¹, Yaqiang Huang², Xiangming Mao⁴, Jianming Lu⁵, Chuanfan Zhong⁶

Affiliations

¹ Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
² Department of Urology, Zhongshan City People's Hospital, Guangdong Medical University, Zhongshan, Guangdong, China.
³ Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
⁴ Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: mxm631221@126.com.
⁵ Department of Andrology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China. Electronic address: louiscfc8@gmail.com.
⁶ Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: icon1994@i.smu.edu.cn.

PMID: 40602220
DOI: 10.1016/j.molimm.2025.06.011

Abstract

Background: The incidence of renal cell carcinoma (RCC) remains high and continues to rise annually, with the clear cell subtype accounting for the majority of cases histologically. While immunotherapy has partially improved the 5-year relative survival rate, response rates vary due to individual heterogeneity, and the overall prognosis remains poor, particularly for high-stage patients. There is an urgent need to identify novel biomarkers for predicting patient prognosis and immunotherapy efficacy to enable personalized treatment.

Methods: Univariate and multivariate Cox regression analysis were employed to validate the prognostic value of NME4 in clear cell renal cell carcinoma (ccRCC) across four cohorts, followed by functional enrichment analysis to elucidate its biological functions. Cellular experiments were conducted to verify NME4's role in ccRCC proliferation and migration. Furthermore, the TIDE (Tumor Immune Dysfunction and Exclusion) algorithm and external datasets were utilized to investigate NME4's predictive capacity for immunotherapy response, while using the 'IOBR' package to analyze the relationship between NME4 and ccRCC immune microenvironment. Finally, somatic mutation and copy number variation analysis provided multi-omics insights into NME4's molecular mechanisms in ccRCC.

Results: Our study determined the predictive ability of NME4 for ccRCC patient prognosis, and patients with high NME4 expression had worse OS and PFI. Functional enrichment analysis revealed the biological functions of NME4, indicating its involvement in the reprogramming of multiple metabolic pathways. Cellular experiments showed that NME4 promoted the proliferation and migration of ccRCC. The TIDE algorithm and external datasets indicated that low NME4 expression predicts better responses to immunotherapy. Additionally, significant differences were observed between NME4 expression subgroups in multi-omics data analysis based on somatic mutation and copy number variation.

Conclusion: In this study, we validated NME4's prognostic predictive capacity for ccRCC patients. Meanwhile, NME4 is expected to be a molecular marker to guide the precise application of immunotherapy in clinical practice.

Keywords: Clear cell renal cell cancinoma; Immunotherapy; Multi-omics; NME4; Prognosis.