Switching off one protein turns T cells into relentless cancer hunters

Scientists have found a way to make T cells hit harder against cancer by flipping a single metabolic switch. In new mouse studies, disabling a protein called ANT2 pushed these immune cells into a preactivated, “warmed-up” state that helped them fight tumors longer and with more force.

The work, led by Professor Michael Berger at the Hebrew University of Jerusalem with partners in Germany and Texas, takes a different tack from many immunotherapy strategies.

Instead of modifying the tumor, the team reshapes the T cell’s internal power grid – changing how the cells generate and spend energy before they ever encounter cancer.

Cell’s hidden energy valve

Ant2 is part of the mitochondria’s carrier system, a protein that swaps ADP for ATP across the inner membrane. When that gate is blocked in T cells, the cells adjust their energy plan.

The authors report that the T cells behave as if they were already warmed up for a fight. They respond faster and keep going longer during repeated stress.

What changed inside the cells

The altered T cells packed more mitochondria and showed higher spare respiratory capacity, the extra energy headroom cells call on under stress. That reserve has been linked to better survival in hardy T cells.

They also shifted how they balance NAD+, the cell’s electron carrier, steering carbon into routes that keep this cofactor available.

One route leaned on proline biosynthesis, a mitochondrial pathway that helps maintain redox balance when oxygen is limited.

Metabolic signatures matched patterns seen in recently activated T cells. That included more glycolysis and signs of a creatine shuttle that buffers ATP.

Berger summarized the cellular shift by noting that disabling ANT2 caused a major change in how T cells generate and use energy, which in turn made them far more effective at identifying and destroying cancer cells.

Tumor tests confirm gains

The team first tested the cells in dishes against melanoma targets. The reprogrammed cells killed more targets at the same ratios.

They then moved to mice bearing skin tumors. Adoptively transferred T cells preconditioned to lack ANT2 slowed tumor growth more than standard cells.

The treated mice showed smaller tumors by the end of the tests, and the modified cells stayed active longer inside the tumor environment, where energy stress normally weakens immune responses.

Drug shortcut to the same effect

Gene edits are not the only path. The group also used small molecules that inhibit ANT2 and saw similar gains in T cell activation. These compounds pushed the cells into the same activated-like state without permanently altering their DNA.

That matters for translation because medicines can be dosed and reversed. It also allows teams to prepare T cells outside the body and return them ready to work.

This approach gives researchers tighter control over timing and intensity, and it reduces some of the safety concerns that come with permanent genetic changes.

Helping T cells survive cancer

Many modern treatments lean on adoptive cell therapy, T cells expanded or tuned outside the body, then reinfused. 

These methods work best when the cells resist fatigue and stay active in the tumor’s harsh setting. Stronger cells are more likely to persist after transfer, reach the tumor, and deliver steady pressure on malignant tissue.

The tumor microenvironment saps fuel and oxygen. Training cells to live with lower oxidative output could help them push through that stress.

It also prepares them for the chemical signals inside tumors that normally weaken immune responses and slow cell growth.

By entering the body with a preconditioned metabolic program, the modified T cells stand a better chance of sustaining their activity over time.

Clues from the cell’s response

ANT2 normally moves ADP and ATP across the mitochondrial inner membrane. When blocked, the T cells restrict OXPHOS, the oxygen-powered ATP-making system, and compensate by adding mitochondrial mass and rerouting carbon.

The result is a cell that has more reserve and stays responsive to signals. In mice, that translated into more potent antitumor activity after transfer.

T cell safety and strength

Safety comes first, especially because ANT2 proteins operate in many tissues. Any systemic drug would require careful dosing and monitoring to avoid unwanted effects.

For cell therapy, a brief preconditioning step offers a cleaner option: it can imprint the metabolic program without exposing the rest of the body to off-target risks.

These cautions sit alongside a wider scientific story. Spare respiratory capacity has long marked resilient T cells, and the new work boosts that reserve by targeting a mitochondrial transporter rather than signaling pathways.

Proline metabolism also emerges as a pressure valve for redox balance in fast-growing cells. In this study, the same mechanism appears to prime immune cells for work in low-oxygen zones where tumors tend to weaken normal immune responses.

The study is published in Nature.

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