Resident Macrophage‐Orchestrated Immune and Fibroblast Interactions in Immune Checkpoint Inhibitor‐Associated Nephrotoxicity

Abstract Immune checkpoint inhibitors (ICIs) transform cancer therapy but are often associated with immune‐related adverse events, including ICI‐associated nephrotoxicity (ICI‐AN). The mechanisms driving ICI‐AN remain poorly understood, limiting diagnostic and therapeutic progress. This study integrates imaging mass cytometry, transcriptomics, and murine models to investigate the cellular and molecular mechanisms driving ICI‐AN. Kidney biopsies from ICI‐AN patients show increased resident macrophages, fibroblasts, and CD8⁺ T cells, with resident macrophages exhibiting elevated pro‐inflammatory and pro‐fibrotic markers. In mice, anti‐PD‐1 treatment induces renal injury characterized by immune cell infiltration, tubular injury, and fibrosis. Depletion of resident macrophages reduces CXCL9 and MMP12 expression, alleviating renal injury without compromising anti‐tumor effects. Transcriptomic analysis confirms that inflammatory and fibrotic pathways involving CXCL9 and MMP12 are central to ICI‐AN pathogenesis. Urinary CXCL9 levels are significantly elevated in ICI‐AN patients, correlating with tubular injury and resident macrophage abundance, while MMP12 expression is predominantly localized to resident macrophages. Pharmacological inhibition of MMP12 mitigates renal injury. These results highlight resident macrophages as central drivers of ICI‐AN and identify CXCL9 as a potential diagnostic biomarker and MMP12 as a therapeutic target. This study provides new insights into ICI‐AN pathogenesis and offers strategies to mitigate nephrotoxicity.