Targeting Acod1/itaconate in cancer therapy: Mechanisms and opportunities

Globally, cancer claims nearly 10 million lives annually, where tumor heterogeneity, the immunosuppressive microenvironment, and therapeutic resistance constitute fundamental clinical challenges. In recent years, immunometabolic reprogramming has emerged as a cutting-edge research frontier, revealing novel mechanisms by which metabolites orchestrate immune responses. Itaconate-an immunometabolite primarily synthesized by macrophages-serves as a pivotal molecular hub bridging metabolic stress and anti-tumor immunity. This review systematically traces the evolution of itaconate from an industrial chemical to a key immunometabolite; comprehensively elucidates its dual roles (pro-tumorigenic vs. anti-tumorigenic) within the tumor microenvironment; synthesizes preclinical evidence of itaconate and its derivatives across diverse tumor systems; and consolidates emerging adjuvant therapeutic strategies targeting the Acod1/itaconate pathway. Collectively, this work aims to provide innovative immunometabolic perspectives for overcoming current barriers in cancer therapy.