Tim-3 Modulation in Immune Responses and Cancer Therapy

T cell immunoglobulin and mucin-domain containing-3 (Tim-3) has emerged as a pivotal immune checkpoint regulator that modulates both innate and adaptive immune responses. Initially described on exhausted CD8+ T cells in chronic infection and cancer, Tim-3 interacts primarily with its ligand galectin-9 to deliver inhibitory signals, driving T cell dysfunction, apoptosis or regulatory phenotypes. Beyond T lymphocytes, Tim-3 is expressed on dendritic cells, monocytes, natural killer cells and regulatory T cells (Tregs), where it influences cytokine production, antigen presentation and cell survival. In the tumour microenvironment, Tim-3 upregulation contributes to immune evasion by promoting exhaustion of cytotoxic T cells and expansion of suppressive Tregs. Therapeutic blockade of Tim-3 or its ligand has shown promise in preclinical models, either as monotherapy or in combination with established checkpoint inhibitors such as PD-1 antagonists. Recent advances have elucidated signalling pathways governing Tim-3 expression, the role of proteolytic shedding in regulating its availability and the crosstalk between Tim-3 and other receptors that shape antitumour immunity. Integrating insights from molecular mechanisms to translational studies underscores the global significance of Tim-3 modulation as a strategy for reinvigorating immune responses against cancer.

Research from Nature Portfolio

Recent studies have revealed that the interaction between galectin-9 and Tim-3 is intricately regulated by co-expressed PD-1, whereby PD-1 binding to galectin-9 attenuates ligand-induced death of Tim-3+ cytotoxic T cells, thereby sustaining a pool of dysfunctional but viable tumour-infiltrating lymphocytes. In models combining galectin-9 blockade with depletion of regulatory T cells via co-stimulatory receptor agonists, synergistic antitumour activity has been observed, highlighting a dual approach that rebalances effector and suppressor compartments within tumours. In parallel, investigation into tumour-infiltrating CD8+ T cells has shown that Tim-3+ populations display heightened effector cytokine secretion yet undergo rapid apoptosis driven by galectin-9. Antibody-mediated inhibition of Tim-3 not only reduces T cell death but also enhances the efficacy of conventional chemotherapeutics, suggesting that co-targeting Tim-3 can improve long-term tumour control.

Tim-3 Modulation in Immune Responses and Cancer Therapy publication trend

The graph below shows the total number of articles in tim-3 modulation in immune responses and cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Tim-3: A transmembrane immune checkpoint receptor expressed on T cells and other immune cells that modulates immune responses through its interactions with specific ligands.

Galectin-9: A carbohydrate-binding ligand for Tim-3 that influences T cell survival and function within the immune system and tumour microenvironment.

T cell exhaustion: A state of T cell dysfunction characterised by progressive loss of effector functions and sustained expression of inhibitory receptors.

Regulatory T cells (Tregs): A subset of T cells with immunosuppressive properties that maintain immune tolerance and modulate antitumour immunity.

Adoptive cell therapy (ACT): A cancer treatment approach that involves the infusion of genetically or functionally modified immune cells to enhance antitumour responses.

Extracellular vesicles: Membrane-bound particles released by cells that carry proteins, nucleic acids and lipids, and mediate intercellular communication.

References

1. Extracellular vesicles derived from nasopharyngeal carcinoma induce the emergence of mature regulatory dendritic cells using a galectin‐9 dependent mechanism. Journal of Extracellular Vesicles (2023).
2. Deletion of the protein tyrosine phosphatase PTPN22 for adoptive T cell therapy facilitates CTL effector function but promotes T cell exhaustion. Journal for ImmunoTherapy of Cancer (2023).
3. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nature Communications (2021).
4. A Disintegrin and Metalloprotease (ADAM) 10 and ADAM17 Are Major Sheddases of T Cell Immunoglobulin and Mucin Domain 3 (Tim-3)*. Journal of Biological Chemistry (2013).
5. An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction. Nature Communications (2015).
6. TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action. International Journal of Molecular Sciences (2017).
7. Tim-3: An Activation Marker and Activation Limiter of Innate Immune Cells. Frontiers in Immunology (2013).