The integrated stress response promotes immune evasion through lipocalin 2
Интегрированный стрессовый ответ способствует уклонению от иммунного надзора посредством липокалина 2
2026-02-18
SCID: 54.1/pv6rpsje
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ATF4–LCN2 axisT cell exclusionimmune evasionintegrated stress responselipocalin 2
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Abstract (AI)
Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR–ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4–LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2. The transcription factor ATF4 and its effector lipocalin 2 (LCN2) have a key role in immune evasion and tumour progression, and targeting the ATF4–LCN2 axis might provide a way to treat several types of solid tumour by increasing anti-cancer immunity.
Key Findings
1
A genetic screen identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector suppressing anti-tumour immune responses.
2
ATF4-driven LCN2 promotes immunosuppressive interstitial macrophage infiltration, T cell exclusion and immune evasion in preclinical tumour models.
3
Anti-LCN2 antibodies induce robust anti-tumour T cell responses in mouse models, supporting the ATF4–LCN2 axis as an immunotherapy target.
4
LCN2 expression correlates with decreased T cell infiltration in human lung and pancreatic adenocarcinomas.
5
Loss of ATF4 substantially reduces tumour progression in immunocompetent, but not immunocompromised, mice by enhancing T cell-dependent anti-tumour immunity.
Research Object
Tumours and tumour–immune interactions governed by the ATF4–LCN2 axis
Research Subject
The ATF4–LCN2-mediated mechanisms of immune evasion, including immunosuppressive macrophage infiltration and T cell exclusion, and their effects on tumour progression and anti-tumour immunity
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2026-02-18
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