Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)
6 affiliations
- 1IRCCS Azienda Ospedaliero-Universitaria di Bologna
- 2Department of Molecular Medicine, University of Pavia
- 3Unit of Radiology, Fondazione IRCCS Policlinico San Matteo
- 4Department of Medical and Surgical Sciences (DIMEC), University of Bologna
- 5Dipartimento Oncologia − Comprehensive Cancer Center, Fondazione IRCCS Policlinico San Matteo
- 6Department of Internal Medicine and Medical Therapy, University of Pavia
Abstract
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the treatment of Non-Small Cell Lung Cancer (NSCLC), yet durable responses remain limited to a minority of patients. Tumor plasticity is increasingly recognized as a determinant of immunotherapy resistance, although the tumor-intrinsic contribution of immunomodulatory mediators such as IFN-γ and PD-L1 remains poorly understood. In this review, we examine emerging evidence that IFN-γ and PD-L1, beyond their established roles in tumor-immune interactions, may contribute to the regulation of NSCLC plasticity. IFN-γ can activate non-canonical programs involving dose-dependent ICAM1/PI3K/AKT/Notch1 signaling, BCAT1- and FGF2/β-catenin-mediated metabolic reprogramming, and a putative autocrine TBX21/IL-4 signaling circuit that may sustain stem-like properties. PD-L1, in turn, is functionally integrated into plasticity-associated pathways involving the TGF-β signaling axis, β-catenin stabilization, epithelial-to-mesenchymal transition-associated microRNA networks, YAP/TAZ, CD44 and ATM signaling, as well as TRAF6/BECN1/NF-κB-dependent regulation of autophagy. Collectively, these findings support a role for IFN-γ and PD-L1 as context-dependent modulators of NSCLC plasticity, with potential implications for immunotherapy resistance, and provide a rationale for further exploring combinatorial treatment strategies and patient stratification approaches.
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BibTeX
@article{angelicola2026beyond,
title = {{Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)}},
author = {Stefania Angelicola and Mariateresa Frascino and Ilaria C. Chillico and Patrick L. S. Michel and Damiano Pistone and Maria Sofia Semprini and Olga Maria Pittino and Andrea Ardizzoni and Niccolò Leandro Alessio and Francesco Agustoni and Francesco Gelsomino and Pier-Luigi Lollini and Arianna Palladini},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1945729},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1945729/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond immune surveillance: IFN-γ and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)
AU - Stefania Angelicola
AU - Mariateresa Frascino
AU - Ilaria C. Chillico
AU - Patrick L. S. Michel
AU - Damiano Pistone
AU - Maria Sofia Semprini
AU - Olga Maria Pittino
AU - Andrea Ardizzoni
AU - Niccolò Leandro Alessio
AU - Francesco Agustoni
AU - Francesco Gelsomino
AU - Pier-Luigi Lollini
AU - Arianna Palladini
PY - 2026
DA - 2026/10/07
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1945729
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1945729/full
AB - Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the treatment of Non-Small Cell Lung Cancer (NSCLC), yet durable responses remain limited to a minority of patients. Tumor plasticity is increasingly recognized as a determinant of immunotherapy resistance, although the tumor-intrinsic contribution of immunomodulatory mediators such as IFN-γ and PD-L1 remains poorly understood. In this review, we examine emerging evidence that IFN-γ and PD-L1, beyond their established roles in tumor-immune interactions, may contribute to the regulation of NSCLC plasticity. IFN-γ can activate non-canonical programs involving dose-dependent ICAM1/PI3K/AKT/Notch1 signaling, BCAT1- and FGF2/β-catenin-mediated metabolic reprogramming, and a putative autocrine TBX21/IL-4 signaling circuit that may sustain stem-like properties. PD-L1, in turn, is functionally integrated into plasticity-associated pathways involving the TGF-β signaling axis, β-catenin stabilization, epithelial-to-mesenchymal transition-associated microRNA networks, YAP/TAZ, CD44 and ATM signaling, as well as TRAF6/BECN1/NF-κB-dependent regulation of autophagy. Collectively, these findings support a role for IFN-γ and PD-L1 as context-dependent modulators of NSCLC plasticity, with potential implications for immunotherapy resistance, and provide a rationale for further exploring combinatorial treatment strategies and patient stratification approaches.
SN - 1664-3224
ER -