TIM-3 in AML: pathogenic roles and therapeutic targetability

Acute Myeloid Leukemia (AML) remains a therapeutic challenge due to immune evasion and relapse. T-cell immunoglobulin and mucin domain-containing-3 (TIM-3) is an immune checkpoint receptor aberrantly expressed on immune cells and leukemic stem cells (LSCs) in AML. Biologically, TIM-3 predominantly mediates deleterious effects, promoting T-cell/NK dysfunction and supporting LSC self-renewal, but this pathogenic expression also makes TIM-3 a therapeutically actionable target. This narrative review synthesizes current preclinical and clinical evidence on the role of TIM-3 in AML. We examined its structure, signaling pathways, and dual functions in promoting immune suppression and LSC self-renewal. A comprehensive analysis of ongoing therapeutic strategies, including monoclonal antibodies and cellular therapies, was conducted. Relevant literature was identified through searches of PubMed, Scopus, and Web of Science databases, with a focus on recently published studies. TIM-3 contributes to immune dysregulation by inducing T-cell exhaustion, impairing NK cell cytotoxicity, and enhancing immunosuppressive myeloid cells. Concurrently, its expression on LSCs drives leukemogenesis through autocrine signaling loops involving Galectin-9 and the β-catenin pathway. Preclinical studies show that TIM-3 blockade reduces leukemic stem-cell frequency and impairs LSC reconstitution in xenograft models, and can reinvigorate anti-leukemic immunity in experimental systems; however, these findings are preclinical and have not yet translated into consistent, randomized clinical benefit in human trials, underscoring the need for biomarker-guided and combination approaches in clinical development (Kikushige et al. Cell Stem Cell 17(3):341–352, 2015; Kikushige et al. Cell Stem Cell7(6):708–717, 2010; Zeidan et al. Lancet Haematol11(1):e38–e50, 2024). Clinically, the anti-TIM-3 antibody sabatolimab showed a tolerable safety profile and preliminary signals of activity when combined with hypomethylating agents; however, randomized phase II data did not demonstrate statistically significant improvements in the primary endpoints (complete response rate and progression-free survival), and the development program has since been re-evaluated in light of these results. TIM-3 also shows promise as a diagnostic and prognostic biomarker. TIM-3 plays an important and multifaceted role in AML pathogenesis, with evidence supporting both immune-regulatory functions and roles in leukemic stem cell biology; however, definitive proof that TIM-3 is essential for LSC maintenance across all AML subtypes requires additional genetic and functional validation. Targeting TIM-3 remains a biologically compelling strategy to address immune suppression and LSC biology in AML, but definitive clinical benefit has not been established in randomized studies to date; further investigation, especially in biomarker-enriched, low-tumor-burden settings and rational combinations, is required to define its clinical role.