A senescence-associated gene signature predicts radiotherapy prognosis in non-small cell lung cancer and identifies CSF1 as a target to potentiate radioimmunotherapy.

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.