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Figure S1-S10 from Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti–PD-1 Immunotherapy

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posted on 2025-05-15, 12:44 authored by Xiao Yang, Yue Deng, Ying Ye, Jingshu Meng, Mengyao Su, Wenwen Wei, You Qin, Haibo Zhang, Yu Tian, Suke Deng, Zhiyun Liao, Zhiyuan Zhou, Jie Li, Yan Hu, Bin Zhang, Yajie Sun, Lu Wen, Zhanjie Zhang, Fang Huang, Chao Wan, Kunyu Yang
<p>Figure S1 shows the metabolic alterations induced by anti-PD-1 treatment in mice. Figure S2 presents the effects of itaconate on anti-PD-1 therapy in vivo. Figure S3 shows the impact of Acod1 deletion on the tumor immune microenvironment. Figure S4 presents the oxidative stress levels in DCs and TAMs within the tumor immune microenvironment. Figure S5 shows the efficiency of immune cell depletion in vivo. Figure S6 demonstrates that the impact of Acod1 deletion on anti-PD-1 therapy is dependent on CD8+ T cells. Figure S7 presents ACOD1 expression patterns in the tumor immune microenvironment. t-SNE projections and violin plots illustrate ACOD1 expression across myeloid and immune cell clusters in lung adenocarcinoma samples. Figure S8 shows the transcriptional regulation of Acod1 via the IFN-γ-JAK/STAT1 axis. Figure S9 presents the inhibitory effects of itaconate on DC antigen cross-presentation. Figure S10 shows the effects of itaconate on DC metabolism and signaling pathways.</p>

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the National Natural Science Foundation of China

National Natural Science Foundation of China (NSFC)

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ARTICLE ABSTRACT

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti–PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell–derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK–STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti–PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti–PD-1 resistance, providing a promising strategy for combination therapy.Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.

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