In a groundbreaking study published recently in Nature, researchers from NYU Langone Health have unveiled a sophisticated mechanism by which certain aggressive tumors, including those in the lung and pancreas, evade the immune system. The discovery centers on a protein called lipocalin 2 (LCN2), produced by cancer cells under chronic stressful conditions, which acts as a molecular shield to help tumors dodge immune attack. This new understanding reveals promising therapeutic avenues aimed at disabling this immune evasion tactic, potentially transforming the treatment landscape for immunotherapy-resistant cancers.
Cancer cells are notorious for their relentless growth and survival under adverse conditions such as nutrient scarcity and hypoxia. To manage these hostile microenvironments, they activate a cellular survival mechanism known as the integrated stress response (ISR). This pathway adapts cellular functions to stressors and is crucial for cancer progression. At the heart of ISR activation is the transcription factor Activating Transcription Factor 4 (ATF4), which orchestrates the expression of numerous genes that collectively enhance cancer cell survival, metabolism, and proliferation under stress.
The NYU Langone research team focused on the relationship between ISR and immune evasion, delving into how ATF4 influences tumor-immune interactions. Their findings revealed that ATF4 stimulates the secretion of LCN2, a small soluble protein, which is secreted outside the cancer cells and plays a pivotal role in subverting the immune response. LCN2 works by modulating the behavior of macrophages—immune cells abundant in the tumor microenvironment—shifting them towards an immunosuppressive phenotype that actively excludes cytotoxic T cells, which are essential for tumor eradication.
This immunosuppressive shift orchestrated by LCN2 essentially builds a protective barrier, preventing immune cells from penetrating the tumor mass and attacking malignant cells. Unlike ATF4, which functions intracellularly and is thus challenging to target pharmacologically, LCN2 exists in the extracellular space where it is more accessible to therapeutic intervention. The researchers harnessed this feature to develop an antibody that neutralizes LCN2, effectively disarming its immune-suppressive capabilities.
Preclinical trials in mouse models of lung and pancreatic cancers demonstrated that blocking LCN2 not only halted tumor progression but also facilitated a resurgence of immune cell infiltration, especially reactivating the tumor-killing T cells. These results were even more compelling when the anti-LCN2 antibody was combined with existing immunotherapies, significantly prolonging survival in aggressive cancer models. This synergistic effect underscores the potential for LCN2-targeted therapies to overcome resistance mechanisms that have limited the efficacy of conventional immune checkpoint inhibitors.
Further substantiating the clinical relevance, tumor sample analyses from over a hundred lung cancer patients and several dozen pancreatic cancer patients showed a clear correlation between elevated LCN2 levels and poorer survival outcomes. Patients exhibiting high LCN2 expression had a median survival rate markedly lower than those with minimal expression, suggesting that LCN2 might serve as a prognostic biomarker and a determinant of immunotherapy responsiveness.
The mechanistic insight into how stressed cancer cells enlist LCN2 to manipulate the immune microenvironment opens a novel front in oncology research. It shifts the paradigm from solely focusing on tumor cells to considering how cancer-related stress pathways influence immune cell behavior, particularly macrophages. Understanding this crosstalk is essential for designing interventions that restore immune surveillance and enhance the effectiveness of immunotherapies.
The study was spearheaded by Dr. Thales Papagiannakopoulos and Dr. Shohei Koide, experts in pathology and molecular pharmacology, respectively. They emphasized that while their current research centered on lung and pancreatic cancers, the involvement of ISR and LCN2 in immune evasion could be a broader phenomenon applicable to various cancer types that presently resist immunotherapy. Their ongoing work aims to investigate this possibility, potentially extending the therapeutic benefits of LCN2 inhibition.
What sets this discovery apart is the dual advantage of targeting LCN2: it not only disrupts a key immune escape mechanism but also sensitizes tumors to existing immunotherapeutic agents. This dual-attack strategy may pave the way for personalized cancer treatments that adapt to the tumor’s molecular stress profile, thwarting its ability to hide from immune detection.
The implications of these findings extend beyond therapeutics into the realm of cancer diagnostics. LCN2 levels in tumors could become part of the diagnostic arsenal to stratify patients according to their likelihood of responding to immunotherapies. Such precision medicine approaches are vital in optimizing clinical outcomes and avoiding unnecessary treatments.
Funding for this pivotal research came from multiple National Institutes of Health grants, the American Cancer Society, the National Science Foundation, and several philanthropic organizations, underscoring the high priority and collaborative nature of cancer research. The authors have declared relationships with various pharmaceutical and biotech companies, managed in accordance with institutional policies to ensure scientific integrity.
NYU Langone Health’s integrated system of research, clinical care, and education provides a fertile environment for such high-impact studies, reflecting its standing as a leading academic medical center. The Perlmutter Cancer Center, central to this research, continues to push the boundaries of knowledge to develop next-generation cancer therapies.
As the oncology community digests these findings, the future looks promising for exploiting the ISR-LCN2 axis to unlock tumors from their immunosuppressive cocoons. This study not only advances scientific understanding but also inspires a new wave of therapeutic innovations aimed at tipping the balance in favor of the immune system and improving survival for patients battling some of the most formidable cancers.
Subject of Research: Human tissue samples
Article Title: ‘The integrated stress response promotes immune evasion through lipocalin 2’
News Publication Date: 18-Feb-2026
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DOI Link to Article
Keywords: Cancer, Transcription factors
