Naringenin in pancreatic cancer: emerging evidence on the tumor immune-stromal microenvironment, immunometabolic reprogramming, microbiota-host crosstalk, and therapeutic resistance
- 1Key Laboratory for Molecular Enzymology of the Ministry of Education, School of Life Sciences, Jilin University
Abstract
Pancreatic cancer continues to be among the deadliest malignancies because of its aggressive biology, dense stromal structure, profound immunosuppression, and restricted responsiveness to existing treatment approaches. Accumulating evidence indicates that effective intervention likely depends on coordinated regulation of the tumor immune–stromal microenvironment, metabolic plasticity, and host–tumor interactions, rather than on malignant-cell targeting alone. Naringenin, a naturally occurring citrus flavanone, has received increasing attention due to its wide-ranging biological effects, including anti-inflammatory, antioxidant, immunomodulatory, and metabolic regulatory activities. This narrative review critically evaluates the current evidence on the molecular mechanisms through which naringenin affects pancreatic cancer progression, with a particular focus on tumor immune–stromal interactions, immunometabolic reprogramming, microbiota–host signaling, and therapeutic resistance. We examine its effects on oncogenic signaling pathways, immune cell function, cancer-associated fibroblasts, extracellular matrix remodeling, oxidative stress, mitochondrial homeostasis, and regulated cell death, while emphasizing growing evidence that connects dietary polyphenols with gut microbiota-derived metabolites and systemic immune regulation. The review also assesses the potential of naringenin as an adjuvant to conventional chemotherapy, targeted therapy, and immunotherapy, while recognizing the constraints arising from low bioavailability, heterogeneous preclinical models, and limited clinical evidence. Finally, we highlight key knowledge gaps and outline future research priorities, including biomarker-guided patient stratification, advanced drug delivery systems, and translational studies that combine multi-omics technologies with mechanistic investigations. Improved understanding of these interrelated mechanisms may support the rational development of naringenin-based therapeutic strategies for pancreatic cancer.
Related
- Decoding lipid metabolic reprogramming in pancreatic ductal adenocarcinoma: from tumor–microenvironment crosstalk to therapeutic resistance
- Immunometabolic reprogramming: a working framework for disease development, endotype differentiation, and therapeutic considerations in pediatric asthma
- Disruption of ACTG1 potentiates anti-TIM-3 immunotherapy by reprogramming the immunosuppressive microenvironment via the CSF3/CSF3R axis in pancreatic cancer
- Engineering clinically actionable nanomedicine for cancer immunometabolic ecosystem reprogramming
- ApoE lipidation state directs immunometabolic reprogramming of human microglia
BibTeX
@article{zhou2026naringenin,
title = {{Naringenin in pancreatic cancer: emerging evidence on the tumor immune-stromal microenvironment, immunometabolic reprogramming, microbiota-host crosstalk, and therapeutic resistance}},
author = {Yuqi Zhou},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1955015},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1955015/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Naringenin in pancreatic cancer: emerging evidence on the tumor immune-stromal microenvironment, immunometabolic reprogramming, microbiota-host crosstalk, and therapeutic resistance
AU - Yuqi Zhou
PY - 2026
DA - 2026/10/20
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1955015
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1955015/full
AB - Pancreatic cancer continues to be among the deadliest malignancies because of its aggressive biology, dense stromal structure, profound immunosuppression, and restricted responsiveness to existing treatment approaches. Accumulating evidence indicates that effective intervention likely depends on coordinated regulation of the tumor immune–stromal microenvironment, metabolic plasticity, and host–tumor interactions, rather than on malignant-cell targeting alone. Naringenin, a naturally occurring citrus flavanone, has received increasing attention due to its wide-ranging biological effects, including anti-inflammatory, antioxidant, immunomodulatory, and metabolic regulatory activities. This narrative review critically evaluates the current evidence on the molecular mechanisms through which naringenin affects pancreatic cancer progression, with a particular focus on tumor immune–stromal interactions, immunometabolic reprogramming, microbiota–host signaling, and therapeutic resistance. We examine its effects on oncogenic signaling pathways, immune cell function, cancer-associated fibroblasts, extracellular matrix remodeling, oxidative stress, mitochondrial homeostasis, and regulated cell death, while emphasizing growing evidence that connects dietary polyphenols with gut microbiota-derived metabolites and systemic immune regulation. The review also assesses the potential of naringenin as an adjuvant to conventional chemotherapy, targeted therapy, and immunotherapy, while recognizing the constraints arising from low bioavailability, heterogeneous preclinical models, and limited clinical evidence. Finally, we highlight key knowledge gaps and outline future research priorities, including biomarker-guided patient stratification, advanced drug delivery systems, and translational studies that combine multi-omics technologies with mechanistic investigations. Improved understanding of these interrelated mechanisms may support the rational development of naringenin-based therapeutic strategies for pancreatic cancer.
SN - 1664-3224
ER -