Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy.

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.