Irradiated CAF-like cells enhance nasopharyngeal carcinoma survival and radioresistance via PI3K/AKT/DNA-PKcs axis
Abstract
Cancer-associated fibroblasts (CAFs) are key stromal cells in the tumor microenvironment (TME) and play critical roles in tumor progression and radioresistance. Radiotherapy kills malignant cells but also triggers stress in CAFs, which alters their phenotype and affects nearby tumor cells. However, how irradiated CAFs influence the survival and radioresistance of nasopharyngeal carcinoma (NPC) cells remains unclear. Human embryonic lung fibroblasts (WI-38) were induced into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) stimulation and then exposed to a single 6 Gy dose. HONE-1 cells were co-cultured with irradiated (irCAFs) or non-irradiated CAF-like cells (iCAFs). The CAF-like phenotype was characterized by reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot (WB), and immunofluorescence (IF). Radiosensitivity was assessed using colony formation assays. CAF-like cell-secreted factors were quantified by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to analyze cell cycle distribution and apoptosis. The mechanisms underlying radioresistance were explored using RNA sequencing. In vivo experiments were conducted with a subcutaneous xenograft mouse model. IrCAFs developed a senescence-associated secretory phenotype (SASP) and significantly increased IL-8 secretion. IL-8 activated the PI3K/AKT signaling pathway in NPC cells, leading to DNA-PKcs phosphorylation and p27 degradation, thereby enhancing NPC cell survival and radioresistance in vitro and in vivo. Neutralization of IL-8 with MAB208 or inhibition of AKT with MK-2206 restored radiosensitivity and improved radiotherapy efficacy. IrCAFs promote NPC cell survival and radioresistance through the IL-8/PI3K/AKT/DNA-PKcs axis. Targeting AKT could enhance radiotherapy efficacy in NPC, offering a potential therapeutic strategy for overcoming radioresistance.
Related
- Smoking exposure and overall survival in nasopharyngeal carcinoma: a multicenter cohort from non-endemic northern China with an exploratory meta-analysis
- Estimating Individualized Survival Benefit of Consolidative Metastasis-Directed Radiotherapy Following Chemoimmunotherapy in Nasopharyngeal Carcinoma With Exclusive Distant Metastasis.
- The Effect of Fine (PM2.5) and Coarse (PM10-2.5) Particulate Matter on Survival Outcomes in Nasopharyngeal Carcinoma Patients: A Retrospective Cohort Study in a Northern Thailand Tertiary Care Center.
- Multi-task deep learning integrating pretreatment MRI and whole slide images predicts induction chemotherapy response and survival in locally advanced nasopharyngeal carcinoma
- Incidence of Osteoradionecrosis and Dental Implant Survival in Patients With Irradiated Head and Neck Malignancies: A Systematic Review and Meta-Analysis
BibTeX
@article{zheng2026irradiated,
title = {{Irradiated CAF-like cells enhance nasopharyngeal carcinoma survival and radioresistance via PI3K/AKT/DNA-PKcs axis}},
author = {Linhui Zheng and Nuomin Liu and Zhenpeng Zhao and Jingtian Yu and Shiyu Cheng and Dong Liu and Yue Liu and Yuan Ke and Chaoyan Wu and Haijun Yu},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-73373-2},
url = {https://www.nature.com/articles/s41598-026-73373-2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Irradiated CAF-like cells enhance nasopharyngeal carcinoma survival and radioresistance via PI3K/AKT/DNA-PKcs axis
AU - Linhui Zheng
AU - Nuomin Liu
AU - Zhenpeng Zhao
AU - Jingtian Yu
AU - Shiyu Cheng
AU - Dong Liu
AU - Yue Liu
AU - Yuan Ke
AU - Chaoyan Wu
AU - Haijun Yu
PY - 2026
DA - 2026/09/30
JO - Scientific Reports
DO - 10.1038/s41598-026-73373-2
UR - https://www.nature.com/articles/s41598-026-73373-2
AB - Cancer-associated fibroblasts (CAFs) are key stromal cells in the tumor microenvironment (TME) and play critical roles in tumor progression and radioresistance. Radiotherapy kills malignant cells but also triggers stress in CAFs, which alters their phenotype and affects nearby tumor cells. However, how irradiated CAFs influence the survival and radioresistance of nasopharyngeal carcinoma (NPC) cells remains unclear. Human embryonic lung fibroblasts (WI-38) were induced into a CAF-like phenotype by transforming growth factor-β1 (TGF-β1) stimulation and then exposed to a single 6 Gy dose. HONE-1 cells were co-cultured with irradiated (irCAFs) or non-irradiated CAF-like cells (iCAFs). The CAF-like phenotype was characterized by reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot (WB), and immunofluorescence (IF). Radiosensitivity was assessed using colony formation assays. CAF-like cell-secreted factors were quantified by enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to analyze cell cycle distribution and apoptosis. The mechanisms underlying radioresistance were explored using RNA sequencing. In vivo experiments were conducted with a subcutaneous xenograft mouse model. IrCAFs developed a senescence-associated secretory phenotype (SASP) and significantly increased IL-8 secretion. IL-8 activated the PI3K/AKT signaling pathway in NPC cells, leading to DNA-PKcs phosphorylation and p27 degradation, thereby enhancing NPC cell survival and radioresistance in vitro and in vivo. Neutralization of IL-8 with MAB208 or inhibition of AKT with MK-2206 restored radiosensitivity and improved radiotherapy efficacy. IrCAFs promote NPC cell survival and radioresistance through the IL-8/PI3K/AKT/DNA-PKcs axis. Targeting AKT could enhance radiotherapy efficacy in NPC, offering a potential therapeutic strategy for overcoming radioresistance.
SN - 2045-2322
ER -