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<p>The optimal strategy for combining radiotherapy (RT) and immunotherapy remains under intensive investigation. Here we developed TRIDENT (<Emphasis Type="Underline">T</Emphasis>riple <Emphasis Type="Underline">R</Emphasis>adio-<Emphasis Type="Underline">I</Emphasis>mmunotherapy-<Emphasis Type="Underline">D</Emphasis>riven <Emphasis Type="Underline">EN</Emphasis>hanced <Emphasis Type="Underline">T</Emphasis>herapy), 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<sup>+</sup> neutrophil-effector CD8<sup>+</sup> 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<sup>+</sup> neutrophils as a promising therapeutic strategy to enhance antitumor efficacy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月7日

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  • Laiyan Zhou,
  • Yuanxin Liu,
  • Zherui Xing,
  • Yuanjun Wu,
  • Xue Yang,
  • Siyuan Chen,
  • Kai Kang,
  • Min Wang,
  • Zhipeng Zhou,
  • Meijuan Huang,
  • Youling Gong,
  • Lin Zhou,
  • Xiaojuan Zhou,
  • Jiangping Li,
  • Zhuoran Yao,
  • Qin Zheng,
  • Feng-Ming Spring Kong,
  • Gabriele Niedermann,
  • Ren Luo,
  • You Lu,
  • Jianxin Xue

摘要

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.