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

Abstract

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. 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. 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. IL8+ TAMs represent a metabolically reprogrammed and immunosuppressive subset driving ICB resistance in ccRCC. Targeting IL8 may overcome resistance and enhance immunotherapy efficacy.