Evidence map›Paper›PMID 41956993›Full record

ArticleSignal transduction and targeted therapy2026

Cortisol-resistant CAR-NK cells overcome steroid-induced immunosuppression in lung cancer.

Soura Chakraborty, Jhuma Pramanik, Gustavo Alviter-Raymundo, Christopher J Ward, Sanu K Shaji, Yumi Yamashita-Kanemaru, Fatma Abo Zakaib Ali, Debasis Banik, Ziwei Zhang, Clara Veiga-Villauriz and 14 more

Abstract read
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In one paragraph

Article in Signal transduction and targeted therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

24 authors.

Soura ChakrabortyDepartment of Pathology, University of Cambridge, Cambridge, UK.
Jhuma PramanikDepartment of Pathology, University of Cambridge, Cambridge, UK.
Gustavo Alviter-RaymundoDepartment of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
Christopher J WardDepartment of Pathology, University of Cambridge, Cambridge, UK.
Sanu K ShajiDepartment of Pathology, University of Cambridge, Cambridge, UK.
Yumi Yamashita-KanemaruDepartment of Pathology, University of Cambridge, Cambridge, UK.ORCID http://orcid.org/0000-0002-2475-8858
Fatma Abo Zakaib AliDepartment of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
Debasis BanikYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Ziwei ZhangYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Clara Veiga-VillaurizDepartment of Pathology, University of Cambridge, Cambridge, UK.
Natalie Z M HomerMass Spectrometry Core, Edinburgh Clinical Research Facility, Institute for Neuroscience and Cardiovascular Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Joanna SimpsonMass Spectrometry Core, Edinburgh Clinical Research Facility, Institute for Neuroscience and Cardiovascular Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Sofia LaforestMass Spectrometry Core, Edinburgh Clinical Research Facility, Institute for Neuroscience and Cardiovascular Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Shanlin TongDepartment of Pathology, University of Cambridge, Cambridge, UK.
Qiuchen ZhaoDepartment of Pathology, University of Cambridge, Cambridge, UK.
James RoyDepartment of Haematology, University of Cambridge, Puddicombe Way, Cambridge, UK.ORCID http://orcid.org/0000-0001-9178-8953
Muhammad IqbalDepartment of Pathology, University of Cambridge, Cambridge, UK.
Andrew Conway MorrisDepartment of Pathology, University of Cambridge, Cambridge, UK.
Michael A ChapmanDepartment of Haematology, University of Cambridge, Puddicombe Way, Cambridge, UK.
Rahul RoychoudhuriDepartment of Pathology, University of Cambridge, Cambridge, UK.
Hosni HusseinDepartment of Pathology, University of Cambridge, Cambridge, UK.
David KlenermanYusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
Kourosh Saeb-ParsyDepartment of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
Bidesh MahataDepartment of Pathology, University of Cambridge, Cambridge, UK. bm562@cam.ac.uk.ORCID http://orcid.org/0000-0002-4506-0184

Funding

Cancer Research UK (CRUK) RCCFEL\100095)RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) BB/V006126/1RCUK | Medical Research Council (MRC) MR/V028995/1
6 · The paper itself

Abstract

Tumors foster an immunosuppressive microenvironment to evade the antitumor immune response. However, the influence of intratumoral immunosuppressive steroids on tumor-infiltrating natural killer (NK) cells and their implications for effective immunotherapy has remained largely unexplored. Here, we report that the functional enrichment of glucocorticoid cortisol signaling in the lung tumor microenvironment (TME) impairs NK cell anti-tumor cytotoxicity and exacerbates hypoxic stress. Cancer-associated fibroblasts (CAFs) and macrophages convert inactive cortisone to active cortisol, while T cells, fibroblasts, myeloid cells, macrophages, and cancer cells contribute to de novo steroid biosynthesis, collectively establishing a steroid-rich niche. Pharmacological inhibition of the glucocorticoid receptor (GR) in vivo alleviates cortisol-mediated immune suppression, resulting in reduced tumor growth and enhanced cytotoxicity of tumor-infiltrating NK cells. To overcome the cortisol-induced dysfunction of solid tumor targeting immunotherapy, we engineered chimeric antigen receptor (CAR) -NK cells specific to the Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (highly expressed in lung tumors) and rendered them cortisol-resistant by genetic deletion of the cortisol receptor gene NR3C1. In cortisol-rich niches, cortisol-resistant CAR-NK cells sustained antitumor cytotoxicity. Mechanistically, NR3C1 deletion relieved cortisol-mediated suppression of PI3K-AKT-NF-κB signaling, restored anti-tumor activity, and markedly reduced hypoxic stress. In lung metastasis models, cortisol-resistant CAR-NK cells achieved superior tumor control and significantly reduced tumor burden compared with conventional CAR-NK cells. Together, these findings identify local cortisol signaling as a critical barrier to solid tumor immunotherapy and establish cortisol-resistant CAR-NK cells as a promising strategy for targeting steroidogenic solid tumors, which can be combined with therapeutic glucocorticoids.

Indexed as

HydrocortisoneKiller Cells, NaturalLung NeoplasmsReceptors, Chimeric AntigenAnimalsCell Line, TumorHumansMiceReceptors, GlucocorticoidSignal TransductionTumor MicroenvironmentHydrocortisoneReceptors, Chimeric AntigenReceptors, Glucocorticoid

Identifiers

PMID41956993
PMCPMC13066642

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.