Protein Tyrosine Phosphatases in Cancer and Metabolic Regulation

Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that remove phosphate groups from tyrosine residues on target proteins, thereby modulating signal transduction pathways fundamental to cell proliferation, differentiation and metabolism. Dysregulation of PTP activity contributes to oncogenesis through altered growth factor and immune signalling, while in metabolic tissues PTPs fine-tune insulin and leptin receptor cascades to maintain glucose and lipid homeostasis. Emerging evidence highlights the dual roles of specific PTPs as tumour suppressors or oncogenic drivers, and as critical regulators of energy balance. Therapeutic strategies now aim to inhibit or degrade selected PTPs to enhance anti-tumour immunity or restore insulin sensitivity, underscoring their global significance in human health.

Research from Nature Portfolio

Recent studies have unveiled first-in-class active-site inhibitors of key immune-regulatory PTPs. One orally bioavailable compound targeting PTPN2 and PTPN1 amplifies interferon responses, remodels the tumour microenvironment and potentiates natural killer and CD8+ T-cell activity in models refractory to checkpoint blockade. A related small molecule selectively inhibits PTP1B and PTPN2 to enhance T-cell recruitment, sensitize ‘cold’ tumours to PD-1 therapy and suppress tumour growth without overt toxicity. These advances demonstrate that targeting the catalytic pockets of intracellular PTPs can yield potent immunotherapeutic agents with the potential to overcome resistance to existing treatments.

Protein Tyrosine Phosphatases in Cancer and Metabolic Regulation publication trend

The graph below shows the total number of articles in protein tyrosine phosphatases in cancer and metabolic regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Protein Tyrosine Phosphatase (PTP): Enzyme that catalyses removal of phosphate from phosphotyrosine residues.

Tumour Microenvironment: Cellular and molecular milieu surrounding cancer cells that influences growth and immune evasion.

JAK–STAT Signalling: Cytokine-activated pathway transmitting extracellular cues to gene transcription via STAT phosphorylation.

Active-Site Inhibitor: Small molecule that binds directly to the catalytic pocket of an enzyme to block activity.

SH2 Domain: Structural motif in signalling proteins that recognises and binds phosphorylated tyrosine motifs.

Ubiquitination: Post-translational attachment of ubiquitin to target proteins, marking them for proteasomal degradation.

References

1. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature (2023).
2. A small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity. Nature Communications (2023).
3. Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T‐Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy. Angewandte Chemie International Edition (2023).
4. Protein-tyrosine Phosphatase 1B Expression Is Induced by Inflammation in Vivo. Journal of Biological Chemistry (2008).
5. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood (2006).