靶向 PERP 通过调节肿瘤免疫微环境和代谢稳态促进头颈部鳞状细胞癌的抗肿瘤免疫。

Targeting PERP promotes anti-tumor immunity in HNSCC by regulating tumor immune microenvironment and metabolic homeostasis.

作者信息

Wang Xueying, Tian Yuxi, Wu Xiaohong, Zhu Yewen, Chen Huihong, Wang Zeyao, Liu Zihan, Tan Jiaqi, Pan Zhaoyu, Cao Jiaoyan, Li Zhenjiang, Zhang Xin, Shi Zhongjie, Wang Juncheng, Liu Tong

机构信息

Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Department of Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, 150000, China.

出版信息

Mol Cancer. 2025 Jun 7;24(1):168. doi: 10.1186/s12943-025-02360-4.

DOI:10.1186/s12943-025-02360-4

PMID:40483487

Abstract

BACKGROUND

PERP may have the potential to function as an oncogene. However, the precise function, prognostic value, and predictive significance remain shrouded in ambiguity.

METHODS

We conducted an in-depth analysis using pan-cancer RNA sequencing data and various online web tools to investigate the correlation between PERP and crucial clinical outcomes such as prognosis, tumor microenvironment, and tumor metabolism. In addition, we explored the tumor-promoting role of PERP and its potential mechanisms through models such as immunofluorescence staining, flow cytometry, cell proliferation assays, wound healing assays, cell migration assays, mass spectrometry analysis and isotope tracing. Further in vivo models confirmed the functional consistency of PERP across pan-cancer. Finally, we analyzed the potential of PERP as a predictive factor for immunotherapy sensitivity in a clinical cohort.

RESULTS

PERP exhibits elevated expression in the majority of cancer types and impedes immune cell infiltration as well as immune checkpoint reactivity in pan-cancer. We confirmed that PERP can promote tumor progression by tumor cell proliferation, scratch and transwell experiments. Meanwhile, the absence of PERP restricts the flux of C-glucose into glycolysis and the tricarboxylic acid (TCA) cycle. Importantly, the deficiency of PERP enhances the in vivo anti-tumor efficacy of PD1 monoclonal antibodies. In addition, low PERP expression is highly correlated with the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy.

CONCLUSIONS

PERP represents a promising predictive/diagnostic biomarker and therapeutic target for HNSCC patients.

摘要

背景

PERP可能具有作为癌基因的潜力。然而，其确切功能、预后价值和预测意义仍不明确。

方法

我们使用泛癌RNA测序数据和各种在线网络工具进行了深入分析，以研究PERP与关键临床结果（如预后、肿瘤微环境和肿瘤代谢）之间的相关性。此外，我们通过免疫荧光染色、流式细胞术、细胞增殖试验、伤口愈合试验、细胞迁移试验、质谱分析和同位素示踪等模型，探索了PERP的促肿瘤作用及其潜在机制。进一步的体内模型证实了PERP在泛癌中的功能一致性。最后，我们在一个临床队列中分析了PERP作为免疫治疗敏感性预测因子的潜力。

结果

PERP在大多数癌症类型中表达升高，并在泛癌中阻碍免疫细胞浸润以及免疫检查点反应性。我们通过肿瘤细胞增殖、划痕和transwell实验证实PERP可促进肿瘤进展。同时，PERP的缺失限制了C-葡萄糖进入糖酵解和三羧酸（TCA）循环的通量。重要的是，PERP的缺乏增强了PD1单克隆抗体的体内抗肿瘤疗效。此外，低PERP表达与头颈部鳞状细胞癌（HNSCC）患者对免疫治疗的反应高度相关。