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. Here, 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 interferon (IFN)-γ 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 anti-tumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate (4-OI), suppressed the tumor antigen presentation and cross-priming ability of dendritic cells (DCs), resulting in the impairment of antigen-specific T-cell anti-tumor responses. In summary, these findings identify an IFN-γ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy.