Lactate-Driven IL8+ Tumor-Associated Macrophages Mediate Immunosuppression and Resistance to Immunotherapy in Clear-Cell Renal Cell Carcinoma

Purpose: 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+ TAMs in ccRCC remains poorly defined. In this study, we aimed to define the clinical and functional relevance of IL8+ TAMs in ccRCC. Experimental design: Two in-house and four external RCC cohorts, encompassing more than 1,400 patients, were analyzed to determine the clinical relevance of IL8+ TAMs. Immunofluorescence and IHC were applied to quantify IL8+ TAM infiltration. Mass/flow cytometry and multiomics were used to define their phenotype, metabolic profile, and immune interactions. Ex vivo tumor cultures were performed to test IL8 blockade and combination with anti-PD-1 therapy. Results: High IL8+ TAM infiltration was consistently associated with ICB resistance. Transcriptomic analyses revealed that IL8+ TAMs adopt a glycolysis-associated metabolic program and are responsive to lactate, which directly promotes IL8 expression. Phenotypically, IL8+ TAMs exhibited an immunosuppressive and chemotactic profile that correlated with CD8+ T-cell dysfunction and regulatory T-cell accumulation. Importantly, ex vivo IL8 blockade alleviated CD8+ T-cell exhaustion and synergized with PD-1 inhibition to enhance antitumor immune responses. Conclusions: IL8+ TAMs represent a metabolically reprogrammed and immunosuppressive subset driving ICB resistance in ccRCC. Targeting IL8 may overcome resistance and enhance immunotherapy efficacy.