Recruited Monocyte-Derived Macrophages Drive T Cell Inflammation in Immune Checkpoint Inhibitor-Mediated Pneumonitis

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Background: Immune checkpoint inhibitor-mediated pneumonitis (CIP) constitutes a major toxicity that limits the clinical application of cancer immunotherapy, whereas its underlying mechanisms remain incompletely understood. Current management relies on nonspecific immunosuppressants, lacking precision therapies. Although single-cell RNA sequencing (scRNA-seq) of bronchoalveolar lavage fluid (BALF) has implicated T cell activation and inflammatory myeloid responses in CIP pathogenesis, critical gaps persist regarding interstitial lung immunity and mechanisms governing monocyte/macrophage–T cell co-enrichment and crosstalk. We aimed to delineate the lung immune circuits that drive CIP and to identify targetable monocyte/macrophage–T cell pathways that could be leveraged for precision intervention. Methods: To elucidate CIP pathogenesis, we performed integrated scRNA-seq analysis of BALF from CIP + and CIP − patients with validation in a prospective cohort using flow cytometry, enzyme-linked immunosorbent assay, Western blotting, and quantitative polymerase chain reaction. Mechanistic studies were performed using an established tumor-bearing forkhead box P3–diphtheria toxin receptor–green fluorescent protein ( Foxp3-DTR-GFP ) mouse model of programmed death-1 inhibitor-induced CIP via micro-computed tomography, histopathology, scRNA-seq, flow cytometry, multiplex immunofluorescence, Western blotting, Transwell migration assays, and pharmacologic interventions. Results: In CIP + patient BALF and mouse lung tissues, CD8 + T cells expressing cytotoxic effectors and C-X-C chemokine receptor 3 (CXCR3) expanded concomitantly with distinct C-C chemokine receptor 2 (CCR2) + monocyte-derived macrophages (MoMΦ) exhibiting a highly inflammatory phenotype, while tissue-resident macrophages were markedly reduced. Mouse models revealed that expanded CCR2 + MoMΦ originating from circulation replenished the depleted niche of lung-resident interstitial macrophages. Mechanistically, integrated in silico prediction and experimental validation demonstrated that CCR2 + MoMΦ recruited CD8 + T cells via the C-X-C motif chemokine ligand 9/10 (CXCL9/10)–CXCR3 axis. Conversely, CD8 + T cells drove CCR2 + MoMΦ expansion and pro-inflammatory phenotype via the interferon-γ (IFN-γ) axis, suggesting the existence of a positive feedback loop between these cell types. Pharmacological targeting of CCR2/CCR5 or CXCR3 signaling attenuated pneumonitis, reduced pulmonary CCR2 + MoMΦ infiltration, diminished pathogenic T cell activation and cytotoxicity, and improved survival without compromising antitumor immunity. Conclusions: Our findings establish CCR2 + MoMΦ and the IFN-γ–CXCL9/10–CXCR3 axis as core drivers of CIP pathogenesis and validate their therapeutic targeting potential. This work provides a scientific foundation for developing CIP-specific prevention and treatment strategies.

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