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

Abstract Purpose: Immune checkpoint blockade (ICB) has revolutionized clear cell renal cell carcinoma (ccRCC) therapy, yet resistance remains common. Tumor-associated macrophages (TAMs) shape the tumor-immune interface and contribute to ICB resistance. While IL8 (CXCL8) was known as a chemokine involved in tumor progression, the role of IL8+ TAMs in ccRCC remains poorly defined. Here, 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 over 1400 patients were analyzed to determine the clinical relevance of IL8+TAMs. Immunofluorescence and immunohistochemistry were applied to quantify IL8+TAMs infiltration. Mass/flow cytometry and multi-omics 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+ TAMs 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.