Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming PMID: 42091852

ADC Targets in Oncology

2026-04-10

Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming

Signal Transduct Target Ther. 2026 May 7;11(1):170. doi: 10.1038/s41392-026-02712-6.

Laiyan Zhou ^# ¹ ² , Yuanxin Liu ^# ¹ , Zherui Xing ^# ¹ , Yuanjun Wu ^# ¹ , Xue Yang ^# ³ , Siyuan Chen ⁴ , Kai Kang ¹ ⁵ , Min Wang ¹ , Zhipeng Zhou ⁶ , Meijuan Huang ¹ , Youling Gong ¹ , Lin Zhou ¹ , Xiaojuan Zhou ¹ , Jiangping Li ¹ , Zhuoran Yao ¹ ⁵ , Qin Zheng ⁴ , Feng-Ming Spring Kong ⁷ , Gabriele Niedermann ⁸ ⁹ , Ren Luo ¹⁰ ¹¹ , You Lu ¹² ¹³ , Jianxin Xue ¹⁴ ¹⁵

Affiliations

1. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
2. Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China.
3. Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
4. Department of Laboratory Medicine, Clinical Laboratory Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
5. Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China.
6. Geneplus-Beijing Institute, Beijing, China.
7. Department of Clinical Oncology, University of Hong Kong, Hong Kong, China.
8. Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
9. German Cancer Consortium (DKTK), Partner Site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg, Germany.
10. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
11. Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
12. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
13. Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
14. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [email protected].
15. Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China. [email protected].
# Contributed equally.

Abstract

The optimal strategy for combining radiotherapy (RT) and immunotherapy remains under intensive investigation. Here we developed TRIDENT (Triple Radio-Immunotherapy-Driven ENhanced Therapy), a novel triple-modality regimen combining immunomodulatory low-dose RT (LDRT) to large tumor(s), immunogenic high-dose RT (HDRT) to small tumor(s), and PD-1 blockade. In our phase I trial of 29 patients with treatment-naïve, PD-L1-positive advanced non-small cell lung Cancer (NSCLC), TRIDENT achieved a median overall survival (mOS) of 51.3 months (95% CI, 20.7-not reached), higher than outcomes typically reported with contemporary standard (chemo)immunotherapy. This durable survival signal was corroborated in an independent real-world cohort of 97 patients with advanced lung Cancer (mOS: 41.5 months; 95% CI, 26.3-63.7). Mechanistically, TRIDENT elicited neutrophil-dependent, systemic antitumor immunity and induced a distinct population of antitumor TNF-α⁺ neutrophils marked by increased MHC and costimulatory molecule expression. Neutrophil recruitment was driven by the CXCL-CXCR2 axis, and polarization toward an antitumor state was programmed by treatment-induced IFN-γ and GM-CSF. TNF-α⁺ neutrophils enhanced CD8⁺ T-cell function via ICAM-1-LFA-1 interactions, and adoptive transfer confirmed their intrinsic antitumor activity in vivo. Spatial transcriptomics of patient tumor tissues further identified a TNF-α⁺ neutrophil-effector CD8⁺ T-cell niche after TRIDENT, providing a stimulatory signal to effector CD8⁺ T cells. In line with these mechanistic findings, clinical biomarker analyses linked neutrophil number with prolonged survival. TRIDENT activates an RT-driven neutrophil-CD8⁺ T-cell axis and promotes survival-associated neutrophil activation. These mechanistic insights, coupled with durable survival in our phase I trial, position TRIDENT as a promising strategy for metastatic NSCLC currently undergoing randomized phase II evaluation. Our study also highlights TNF-α⁺ neutrophils as a promising therapeutic strategy to enhance antitumor efficacy.