ABSTRACT Isocitrate dehydrogenase (IDH) mutations represent pivotal oncogenic drivers across multiple malignancies. Mutant IDH enzymes acquire neomorphic activity that produces the oncometabolite D ‐2‐hydroxyglutarate (D‐2HG), which competitively inhibits α‐ketoglutarate‐dependent dioxygenases and promotes epigenetic reprogramming, differentiation arrest, and malignant transformation. Beyond tumor cell–intrinsic effects, D‐2HG profoundly remodels the tumor immune microenvironment by directly suppressing T‐cell proliferation and effector functions, silencing natural killer (NK) cell‐activating ligands, and impairing dendritic cell maturation. In this review, we delineate the mechanistic basis of mutant IDH in oncogenesis and evaluate the development of selective allosteric inhibitors validated through rigorous preclinical models demonstrating potent D‐2HG suppression. Clinical translation has yielded multiple FDA‐approved IDH inhibitors demonstrating significant therapeutic efficacy across diverse IDH‐mutant malignancies. Notably, dual inhibitors have extended progression‐free survival in gliomas, whereas triple‐combination regimens have achieved substantial complete remission rates in acute myeloid leukemia. However, therapeutic resistance has emerged through second‐site mutations, clonal evolution, and metabolic reprogramming. We also discuss rational combinatorial strategies integrating IDH inhibitors with hypomethylating agents (HMAs), targeted therapies, and immunomodulatory approaches, alongside emerging technologies such as single‐cell profiling and spatial transcriptomics. By addressing both achievements and challenges, this review underscores the translational relevance of IDH‐targeted therapy and its potential to reshape precision oncology through refined patient stratification and enhanced therapeutic efficacy.
Fang et al. (Sun,) studied this question.