Authors
Shaochuan Liu, Yuhan Zhang, Liuze Li, Huanhuan Wang, Hao Yuan, Deyi Zhang, Donghe Zhao, Yong Guan, Zhiyong Yuan
Published in
Biology direct. Jul 17, 2026. Epub Jul 17, 2026.
Abstract
The role of cellular senescence as a tumor-associated hallmark and therapeutic target in influencing radiotherapy or radioimmunotherapy outcomes remains incompletely understood. To address this, we developed a senescence-associated gene signature to predict prognosis in non‑small cell lung cancer (NSCLC) patients treated with radiotherapy. A risk model based on nine genes-including COL4A1 and CSF1-effectively stratified patients into high‑ and low‑risk groups. High‑risk patients exhibited significantly poorer overall survival and a tumor microenvironment characterized by reduced immune infiltration and an immune‑excluded phenotype. CSF1 was identified as a pivotal gene within this signature. Mechanistically, radiotherapy induces the expansion of a CSF1‑high‑expressing exhausted T‑cell population, which exhibits characteristics of both exhausted and senescent T cells and forms a positive feedback loop with M2‑like macrophages, thereby reinforcing the immunosuppressive microenvironment. Preclinical studies demonstrated that combining a CSF1‑neutralizing antibody with radiotherapy and anti‑PD‑1 therapy effectively reduced exhausted T cells and M2 macrophages, leading to a significant enhancement in therapeutic efficacy. Taken together, our work establishes a nine‑gene signature for risk stratification in NSCLC and provides proof‑of‑concept that targeting CSF1 can potentiate radioimmunotherapy, offering a novel translational strategy for improving patient survival.
PMID:
42469881
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.
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