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November 4, 2025
by Monash University
edited by Sadie Harley, reviewed by Robert Egan
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Chimeric Antigen Receptor (CAR) T cell therapies have revolutionized cancer treatment—but so far, their success has been largely limited to blood cancers. Solid tumors, which account for around 90% of all adult cancers, remain a major challenge because they are difficult for CAR T cells to infiltrate and are often highly heterogeneous, making them harder to target with a single therapy.
Researchers at Monash University, in collaboration with scientists from the Peter MacCallum Cancer Center, used CRISPR-based gene editing or a PTPN2 inhibitor to enhance the function of human CAR T cells engineered to recognize an antigen expressed on many solid tumors.
The study, led by Professor Tony Tiganis and Dr. Florian Wiede, was published in Science Translational Medicine.
Importantly, the PTPN2 inhibitor used in this research is an investigational compound currently in Phase 1 clinical trials for solid tumors, both as a monotherapy and in combination with anti-PD-1 immunotherapy, where it is designed to elicit the body’s endogenous immune response against cancer.
Like PD-1, which acts as an inhibitory checkpoint that restrains T cell activity, PTPN2 is a key negative regulator of immune cell signaling.
However, while PD-1 functions at the cell surface to limit T cell activation through ligand engagement, PTPN2 acts inside the cell, controlling signaling pathways that determine how strongly and how long T cells remain activated. Because of this, targeting PTPN2 may complement or even amplify the effects of PD-1 blockade, offering a way to both enhance natural anti-tumor immunity and boost CAR T cell efficacy in solid cancers.
The research team found that deleting or inhibiting PTPN2 in CAR T cells reduced tumor size and prolonged survival in mouse models of solid cancer, and also enhanced tumor killing in human in vitro (lab-based) models. This effect appears to be linked to the generation of long-lived stem cell–like CAR T cells that can persist in circulation and continue to eliminate residual cancer cells, potentially lowering the risk of recurrence.
“Targeting PTPN2 led to increased activity and killing capacity of CAR T cells, suppressing tumor growth and prolonging survival in several mouse models of solid cancers,” Professor Tiganis said.
“Importantly, this treatment was associated with the generation of long-term memory T cells capable of persisting in tumors. Altogether, our findings suggest that targeting PTPN2 in CAR T cells may improve treatment responses in patients with solid tumors.”
He cautioned, however, that these results are based on preclinical studies, and further testing in humans will be essential to confirm both safety and efficacy. Because PTPN2 helps regulate immune activity, altering its function could potentially increase the risk of autoimmune or other immune-related adverse effects if not carefully controlled.
Dr. Wiede added, “While cellular therapies have transformed the management of blood malignancies, they have been far less successful in solid tumors. Our data support the concept that gene editing or pharmacological inhibition of PTPN2 could enhance the effectiveness of CAR T cells against solid cancers.”
More information: Xin Du et al, Targeting PTPN2 enhances human CAR T cell efficacy and the development of long-term memory in mouse xenograft models, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adk0627
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Inhibiting or deleting PTPN2 in CAR T cells enhances their ability to target and kill solid tumors, leading to reduced tumor size and prolonged survival in preclinical models. This approach promotes the formation of long-lived, stem cell–like CAR T cells, potentially improving persistence and reducing recurrence. Targeting PTPN2 may complement PD-1 blockade, but safety in humans requires further study.
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