Stress Protein Shields Tumors From Immune System

New drugs targeting lipocalin 2 could make aggressive cancers more vulnerable to immunotherapies.

Published on Feb. 23, 2026

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A new study led by researchers from NYU Langone Health found that a protein called lipocalin 2 (LCN2), produced by stressed cancer cells, helps lung and pancreatic tumors evade the immune system. The researchers designed an antibody therapy to block LCN2, which allowed cancer-killing T cells to enter the tumors and shrank them in mice. Combining the LCN2 antibody with an existing immunotherapy drug worked even better, extending survival in mice with aggressive lung cancer.

Why it matters

The findings provide a clear rationale for developing therapies that target LCN2 in lung cancer patients, as high LCN2 levels were linked to shorter median survival times in lung and pancreatic cancer patients. Unmasking tumors and making them more vulnerable to the immune system could improve outcomes for patients with aggressive cancers that resist immunotherapies.

The details

The study found that the integrated stress response (ISR) pathway in cancer cells triggers the production of a protein called Activating Transcription Factor 4 (ATF4), which in turn instructs the cell to release LCN2 to protect the tumor from the immune system. LCN2 passes on the ATF4 message to switch macrophages, a type of immune cell abundant in tumors, into an "immunosuppressive" mode, keeping cancer-killing T cells from entering the tumor. The researchers designed an antibody therapy to bind and block LCN2, which kept it from manipulating macrophages and allowed the sidelined T cells back into the tumors.

  • The study was published online on February 18, 2026 in the journal Nature.

The players

NYU Langone Health

The research was led by researchers from NYU Langone Health.

Thales Papagiannakopoulos

Thales Papagiannakopoulos, PhD, is the co-corresponding study author and an associate professor in the Department of Pathology at the NYU Grossman School of Medicine.

Shohei Koide

Shohei Koide, PhD, is the co-corresponding study author, a professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, and the director of Cancer Biologics at Perlmutter Cancer Center.

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What they’re saying

“Stressed cancer cells have learned to call for help through LCN2, which shields them from the immune system.”

— Thales Papagiannakopoulos, Associate Professor, Department of Pathology, NYU Grossman School of Medicine (Mirage News)

“Our results provide a clear rationale for developing therapies that target LCN2 in lung cancer patients. We also want to explore whether this mechanism is active in other cancer types that resist immunotherapy.”

— Shohei Koide, Professor, Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, and Director of Cancer Biologics, Perlmutter Cancer Center (Mirage News)

What’s next

The researchers plan to further explore whether the LCN2 mechanism is active in other cancer types that resist immunotherapy, in addition to continuing the development of therapies that target LCN2.

The takeaway

This study provides a promising new approach to making aggressive cancers more vulnerable to immunotherapies by targeting the stress protein LCN2, which helps tumors evade the immune system. Blocking LCN2 could improve outcomes for patients with lung, pancreatic, and other cancers that are resistant to current immunotherapy treatments.