<p>Table S1 presents the sequences of primers used for RT-qPCR analysis. Table S2 lists the sequences of primers used for ChIP-PCR. Table S3 contains the differentially expressed metabolites identified in tumor tissues of Lewis tumor-bearing mice treated with IgG2 (Ctrl) or anti-PD-1 monoclonal antibody. Table S4 summarizes the differentially expressed genes in untreated and IFN-γ-treated bone marrow-derived macrophages (BMDMs). Table S5 provides the differentially expressed genes in bone marrow-derived dendritic cells (BMDCs) under IFN-γ versus IFN-γ + 4-OI treatment conditions.</p>
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.
