Data from Lactate-Driven IL8<sup>+</sup> Tumor-Associated Macrophages Mediate Immunosuppression and Resistance to Immunotherapy in Clear-Cell Renal Cell Carcinoma

作者：Yu Dong, Wenbin Jiang, Youqi Qiu, Ziyang Xu, Jiangting Cheng, Peiqing Ke, Siyuan Dai, Yang Qu, Yu Xia, Jianming Guo, Li Liu, Jiejie Xu · 年份：2026 · DOI：10.1158/1078-0432.c.8542421 · 被引用次数：1 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

<div>AbstractPurpose:<p>Immune checkpoint blockade (ICB) has revolutionized clear-cell renal cell carcinoma (ccRCC) therapy, yet resistance remains common. Tumor-associated macrophages (TAM) shape the tumor–immune interface and contribute to ICB resistance. Although IL8 (CXCL8) was known as a chemokine involved in tumor progression, the role of IL8<sup>+</sup> TAMs in ccRCC remains poorly defined. In this study, we aimed to define the clinical and functional relevance of IL8<sup>+</sup> TAMs in ccRCC.</p>Experimental Design:<p>Two in-house and four external RCC cohorts, encompassing more than 1,400 patients, were analyzed to determine the clinical relevance of IL8<sup>+</sup> TAMs. Immunofluorescence and IHC were applied to quantify IL8<sup>+</sup> TAM infiltration. Mass/flow cytometry and multiomics were used to define their phenotype, metabolic profile, and immune interactions. <i>Ex vivo</i> tumor cultures were performed to test IL8 blockade and combination with anti–PD-1 therapy.</p>Results:<p>High IL8<sup>+</sup> TAM infiltration was consistently associated with ICB resistance. Transcriptomic analyses revealed that IL8<sup>+</sup> TAMs adopt a glycolysis-associated metabolic program and are responsive to lactate, which directly promotes IL8 expression. Phenotypically, IL8<sup>+</sup> TAMs exhibited an immunosuppressive and chemotactic profil...