Kovaleva Olga V, Sinyov Vasiliy V, Rashidova Madina A, Malashenko Olga S, Gratchev Alexei
Institute of Experimenal Oncology and Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.
Center for Molecular and Cell Biology, Skolkovo Institute of Science and Technology, Moscow, Russia.
Front Immunol. 2026 Feb 2;17:1755401. doi: 10.3389/fimmu.2026.1755401. eCollection 2026.
Renal cell carcinoma (RCC) is an immunogenic tumor in which tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) represent a functionally important component of the tumor microenvironment. Recent studies have revealed pronounced phenotypic heterogeneity of RCC-infiltrating neutrophils, including interferon-responsive, immunosuppressive PMN-MDSC-like, pro-angiogenic, and NET-forming subsets that cannot be adequately described by the classical N1/N2 model. Their polarization is shaped by ELR CXC chemokines (CXCL1, CXCL8), cytokine signals, systemic inflammation, hypoxia driven by VHL/HIF pathways, and tumor-intrinsic oncogenic alterations such as PTEN loss, ERβ- and c-Myc-dependent programs, as well as epigenetic remodeling. TANs exert predominantly pro-tumor functions in RCC, promoting T-cell exclusion and exhaustion, supporting angiogenesis and stromal remodeling, and facilitating epithelial-mesenchymal transition, venous invasion and metastasis. NETs, enriched in hypoxic and necrotic tumor regions and in venous tumor thrombi, further contribute to vascular occlusion, metastatic dissemination and local immune dysfunction, and are reflected by distinct transcriptional signatures. Clinically, high TAN density, activation markers and neutrophil/NET-associated gene signatures are consistently associated with aggressive tumor behavior, early recurrence, poor survival and resistance to VEGF-TKIs and immune checkpoint inhibitors. Emerging data also link neutrophil-rich stromal inflammation with the tumor resident microbiome, suggesting composite TAN-microbiome biomarkers for refined risk stratification. In this review, we summarize current knowledge on phenotypic diversity, regulatory circuits and functional programs of TANs and NETs in RCC, and discuss their prognostic and predictive significance, as well as therapeutic strategies aimed at chemokine blockade, complement modulation, NET inhibition and neutrophil re-education.
肾细胞癌（RCC）是一种免疫原性肿瘤，其中肿瘤相关中性粒细胞（TANs）和中性粒细胞胞外陷阱（NETs）是肿瘤微环境中功能上的重要组成部分。最近的研究揭示了RCC浸润性中性粒细胞存在明显的表型异质性，包括干扰素反应性、免疫抑制性PMN-MDSC样、促血管生成和形成NET的亚群，经典的N1/N2模型无法充分描述这些亚群。它们的极化受ELR CXC趋化因子（CXCL1、CXCL8）、细胞因子信号、全身炎症、VHL/HIF途径驱动的缺氧以及肿瘤内在致癌改变（如PTEN缺失、ERβ和c-Myc依赖性程序以及表观遗传重塑）的影响。TANs在RCC中主要发挥促肿瘤功能，促进T细胞排斥和耗竭，支持血管生成和基质重塑，并促进上皮-间质转化、静脉侵犯和转移。NETs在缺氧和坏死肿瘤区域以及静脉肿瘤血栓中富集，进一步导致血管闭塞、转移扩散和局部免疫功能障碍，并由独特的转录特征反映出来。临床上，高TAN密度、激活标志物以及中性粒细胞/NET相关基因特征始终与侵袭性肿瘤行为、早期复发、不良生存以及对VEGF-TKIs和免疫检查点抑制剂的耐药性相关。新出现的数据还将富含中性粒细胞的基质炎症与肿瘤驻留微生物群联系起来，提示复合TAN-微生物群生物标志物可用于精细的风险分层。在本综述中，我们总结了目前关于RCC中TANs和NETs的表型多样性、调控回路和功能程序的知识，并讨论了它们的预后和预测意义，以及旨在趋化因子阻断、补体调节、NET抑制和中性粒细胞再教育的治疗策略。
