Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming
Summary
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
Content
# Low-dose radiotherapy synergizes with PD-1 blockade to achieve durable survival in advanced NSCLC through antitumor neutrophil programming
*Published: 2026 May 7*
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.
DOI: 10.1038/s41392-026-02712-6