Evidence map›Paper›PMID 42593864›Full record

ArticleThe Journal of clinical investigation2026

Tumor NLRP3 amplification promotes immunotherapy resistance by inhibiting STAT1 signaling and MHC class I expression.

Balamayroon Theivanthiran, Nagendra Yarla, Kaylee Villarreal, Y-Van Nguyen, Mahere Rezazade Bazaz, Ernesto Pena Calderin, Linda Cao, Kyra Majors, Michael P Plebanek, Alisha Holtzhausen and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of clinical investigation, 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

5 · Who and what money

Authors and funding

16 authors.

Balamayroon TheivanthiranLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nagendra YarlaDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
Kaylee VillarrealDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
Y-Van NguyenLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Mahere Rezazade BazazLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Ernesto Pena CalderinLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Linda CaoLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Kyra MajorsLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Michael P PlebanekLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Alisha HoltzhausenDepartment of Pharmacology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Emily BolchDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
Douglas B JohnsonDepartment of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Hope UronisDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
John H StricklerDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
Nicholas C DeVitoDuke Cancer Institute, Department of Medicine, Division of Medical Oncology, Duke University, Durham, North Carolina, USA.
Brent A HanksLineberger Comprehensive Cancer Center, Department of Medicine, Division of Medical Oncology, Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Funding

Investigating the PD-L1:NLRP3 signaling axis as a tumor intrinsic mechanism of adaptive resistance to anti-PD-1 antibody immunotherapyR37CA249085 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI HANKS, BRENT ALLEN · 2020 to 2025
$2.5M
NCI NIH HHS R37 CA249085
6 · The paper itself

Abstract

Immunotherapy resistance remains a challenge in immuno-oncology, and predictive biomarkers are needed to guide combination immunotherapy selection for the individual patient. We showed that elevated tumor-intrinsic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) signaling activity correlates with checkpoint inhibitor resistance in several independent cohorts of stage III/IV melanoma and gastroesophageal (GE) adenocarcinoma. In situ hybridization demonstrated tumor NLRP3 copy number gain in immunotherapy-resistant melanomas and GE adenocarcinomas harboring enhanced NLRP3 signaling activity. Nlrp3 amplification suppressed NOD-, LRR-, and CARD-containing 5-mediated (NLRC5-mediated) MHC class I upregulation, while spatial transcriptomic analysis of patient-derived GE adenocarcinomas confirmed that NLRP3 signaling activity inversely correlated with NLRC5 and MHC class I-associated gene expression. Mechanistically, NLRP3 binds to and inhibits signal transducer and activator of transcription 1 (STAT1) dimerization, nuclear translocation, and NLRC5 transcription. Consistent with these findings, pharmacologic inhibition of the NLRP3 inflammasome augmented tumor STAT1/NLRC5 signaling, enhanced MHC class I surface expression, and overcame anti-programmed cell death 1 resistance in an orthotopic model of gastric adenocarcinoma. This work reveals a fundamental link between cellular stress and tumor-mediated immune evasion and indicates that the tumor NLRP3 signaling pathway merits further clinical study as a therapeutic target and a source of companion biomarkers for overcoming checkpoint inhibitor resistance in patients with cancer.

Indexed as

AdenocarcinomaDrug Resistance, NeoplasmGenes, MHC Class IHistocompatibility Antigens Class IImmunotherapyMelanomaNeoplasm ProteinsNLR Family, Pyrin Domain-Containing 3 ProteinSignal TransductionSTAT1 Transcription FactorAnimalsHumansMiceHistocompatibility Antigens Class INeoplasm ProteinsNLR Family, Pyrin Domain-Containing 3 ProteinNLRP3 protein, humanSTAT1 protein, humanSTAT1 Transcription FactorCancer immunotherapyCellular immune responseImmunologyMHC class 1Oncology

Identifiers

PMID42593864
PMCPMC13668618

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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 OpenQuestion graph.