RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
p53 突变对肿瘤免疫逃逸的影响：机制见解与临床意义
英文原题：The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.
查看英文原题
The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.
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中文摘要
突变型p53（Mtp53）不仅丧失其经典的抑癌功能，还获得致癌性功能获得特性，使其成为重塑肿瘤免疫微环境的核心调控者。本综述系统阐述了Mtp53如何通过多种相互关联的机制主动建立并维持免疫抑制生态位，包括慢性炎症、免疫细胞功能障碍、癌症相关成纤维细胞重编程、代谢失调、表观遗传劫持以及可能异常的液-液相分离，从而促进免疫逃逸和治疗耐药。
我们整合现有证据提出一个概念性的“代谢-表观遗传-免疫”轴：Mtp53驱动的代谢重编程——如乳酸或α-酮戊二酸的积累——可调节染色质修饰和免疫基因表达。
值得注意的是，该轴的完整体内因果链尚未建立；现有支持主要来自逐步实验数据和强相关性。Mtp53的免疫学影响高度依赖于背景，受共突变和组织来源的影响。在TP53/KRAS共突变非小细胞肺癌（NSCLC）中，Mtp53增强肿瘤免疫原性并改善对免疫检查点抑制剂（ICIs）的应答；相反，在免疫“冷”肿瘤中——如三阴性乳腺癌、胰腺导管腺癌和结直肠癌——它促进T细胞耗竭或髓系抑制，反映出显著的癌种异质性。治疗策略包括Mtp53再激活剂（如APR-246、PC14586）、降解剂、合成致死策略和新抗原疫苗。尽管APR-246在II期试验（NCT03072043）中显示出疗效，但由于缺乏TP53突变分层，其在III期试验（NCT03745716）中未能改善生存。其与pembrolizumab联合使用（NCT04383938）表现出可接受的安全性（免疫相关不良事件约12%），但疗效有限，凸显了基于生物标志物的精准联合治疗的必要性。
因此，亟需一个多维生物标志物平台——整合TP53突变亚型（如R175H与无义突变）、动态ctDNA监测（VAF ≥ 0.01%）、肿瘤免疫微环境（TIME）特征（如TILs、MDSCs）以及空间多组学——以实现对Mtp53驱动癌症的精准分子分层和个性化干预。
展开英文摘要原文
Mutant p53(Mtp53) not only loses its canonical tumor-suppressive functions but also acquires oncogenic gain-of-function properties, positioning it as a central orchestrator in reshaping the tumor immune microenvironment.
This review systematically delineates how Mtp53 actively establishes and sustains an immunosuppressive niche through multiple interconnected mechanisms, including chronic inflammation, immune cell dysfunction, reprogramming of cancer-associated fibroblasts, metabolic dysregulation, epigenetic hijacking, and potentially aberrant liquid-liquid phase separation, thereby promoting immune evasion and therapeutic resistance.
We integrate current evidence to propose a conceptual "metabolism-epigenetics-immunity" axis: Mtp53-driven metabolic reprogramming-such as accumulation of lactate or α-ketoglutarate-can modulate chromatin modifications and immune gene expression.
Notably, the full in vivo causal chain of this axis remains unestablished; existing support derives primarily from stepwise experimental data and strong correlations. The immunological impact of Mtp53 is highly context-dependent, shaped by co-mutations and tissue origin. In TP53/KRAS co-mutant non-small cell lung cancer (NSCLC), Mtp53 enhances tumor immunogenicity and improves response to immune checkpoint inhibitors (ICIs); conversely, in immunologically "cold" tumors-such as triple-negative breast cancer, pancreatic ductal adenocarcinoma, and colorectal cancer-it promotes T-cell exhaustion or myeloid suppression, reflecting marked cancer-type heterogeneity.
Therapeutic approaches include Mtp53 reactivators (e. g. , APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Although APR-246 showed efficacy in a phase II trial (NCT03072043), it failed to improve survival in phase III (NCT03745716) due to lack of TP53 mutation stratification. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations.
Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e. g. , R175H vs . nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0. 01%), tumor immune microenvironment (TIME) features (e. g. , TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers.
论文信息
- 作者
- Liang L、Wang W
- 第一作者单位
- Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.China
- 通讯作者单位
- Department of Head and Neck Radiation Oncology, Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, China.China
- 文献类型
- 综述
- 期刊
- Frontiers in immunology2026
- 原文标识
- PubMed 41727427 · DOI 10.3389/fimmu.2026.1753215
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