ANN ARBOR, Mich. (Michigan News Source) – University of Michigan researchers have uncovered a key reason why some cancer cells are immune to immunotherapy – the kind that supercharges our own immune system to fight off cancer. The culprit? A protein called SLC13A3, which acts like an invisible shield, stopping cancer cells from dying the way they’re supposed to.

Immunotherapy is a cutting-edge treatment that uses “killer” T cells to destroy cancer cells. These treatments can block “checkpoints” that turn T cells off or even re-engineer them to attack cancer better. While that sounds great to many, the catch is that it only works for some patients.

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Professor Weiping Zou and his team dove into why that happens. “Our goal is to really understand what’s behind this lack of response” Zou explains to the Michigan Daily. “Because if you understand the reasons, we may be able to uncover the factors not only contributing to the resistance to cancer therapy, (but also) we may be able to find the solution.”

The role of a sneaky transporter.

The team focused on metabolites – tiny molecules created during metabolism – and the transporters that move them. They zeroed in on SLC13A3, a protein found in higher levels in tumors resistant to immunotherapy. High SLC13A3 levels were linked to worse survival rates and less effective treatments.

Using mice, the researchers confirmed that tumors with SLC13A3 grew more aggressively, while those without it slowed down. Turns out, this protein protects tumors by stopping ferroptosis, a type of cell death where cancer cells basically poison themselves with toxic fats.

Zou says, “In immunotherapy, when the patient shows therapeutic response, we know some tumor cells, if not all, die through ferroptosis. But most patients are not responsive. That’s why we were assuming there may be mechanisms which allow the tumor cells to escape from ferroptosis.”

Fighting back with succinic acid.

After discovering that SLC13A3 helps shield tumor cells from ferroptosis, Zou explained that the team set out to find a way to inhibit its function, enabling cancer cells to undergo successful cell death.

Their solution: Succinic acid, a small molecule that jams SLC13A3’s function. In lab tests and mouse models, this inhibitor successfully stopped tumor growth, especially when paired with existing treatments.

The future of cancer immunotherapy.

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But don’t get too excited yet – this breakthrough isn’t quite ready for human trials – it’s still “preclinical” according to researcher Tison Lin, who says, “We’re hopeful, but we have to try many avenues.”

Zou believes that the immune system is a very powerful tool to fight cancer, and adds optimistically, “We think if you are able to powerfully equip our immune system, we should be able to combat cancer.”