ATF4 protein helps tumors hide from immune system via Lipocalin 2

ATF4 protein helps tumors hide from the immune system

Cancer cells use a protein called ATF4 to help them grow and survive stressful conditions like chemotherapy. New research now shows this same protein also helps tumors hide from the body's immune system.

A study published in Nature reveals that ATF4 works by activating another protein, Lipocalin 2 (LCN2). This creates a shield around the tumor that blocks cancer-killing T cells.

Immune system is key to the effect

Researchers found that blocking ATF4 in mouse models of lung and pancreatic cancer significantly slowed tumor growth. Crucially, this only worked in mice with intact immune systems.

In immunocompromised mice, blocking ATF4 had little effect. This proved the protein's major role is not in direct tumor growth, but in manipulating the immune environment.

"The ATF4–LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity," the authors concluded. The finding shifts the focus from how cancer cells survive internally to how they defend themselves externally.

LCN2 recruits the tumor's bodyguards

An unbiased genetic screen identified LCN2 as ATF4's key partner. The study found that ATF4-driven LCN2 production recruits specific, immunosuppressive macrophages to the tumor site.

These macrophages act like bodyguards, creating a physical and chemical barrier. This leads to two major outcomes:

• T cell exclusion: Immune cells cannot infiltrate the tumor.
• Immune evasion: The tumor becomes invisible to the body's defenses.

The correlation held in human patients. High LCN2 levels in lung and pancreatic adenocarcinomas were linked to decreased T cell infiltration.

Antibody treatment shows promise in mice

The research points to a direct therapeutic strategy: targeting LCN2. In mouse models of aggressive solid tumors, treatment with anti-LCN2 antibodies broke down the tumor's defenses.

The antibodies disrupted the immunosuppressive environment, allowing a robust anti-tumor T cell response to mount. This stopped tumor progression.

The study suggests that blocking the ATF4-LCN2 pathway could be a viable immunotherapy approach, especially for cancers resistant to current immunotherapies.

A new path for immunotherapy

Most current immunotherapies, like checkpoint inhibitors, aim to re-activate existing T cells that are already at the tumor site but have been switched off. This new research addresses a prior step: getting T cells to the tumor in the first place.

By targeting LCN2, the approach could make "cold" tumors with no T cell presence into "hot" tumors susceptible to attack. This could expand the range of cancers treatable with immunotherapy.

The authors state their work "could pave the way for an immunotherapy approach that targets LCN2." The next steps will involve developing these findings into clinical treatments for human patients.