Pulsed Low-dose-rate Radiotherapy Remodels the Tumor Immune Microenvironment and is Associated With Crosstalk Between SPP1⁺ tumor-associated macrophages and GZMK⁺ CD8⁺ T cells
8 affiliations
- 1Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, China
- 2Fujian Key Laboratory of Intelligent Imaging and Precision Radiotherapy for Tumors (Fujian Medical University), Fuzhou, Fujian China
- 3Clinical Research Center for Radiology and Radiotherapy of Fujian Province (Digestive, Hematological and Breast Malignancies), Fuzhou, Fujian China
- 4Department of Radiation Oncology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian China
- 5Department of Oncology, Jinjiang Hospital of Traditional Chinese Medicine, Jinjiang, Fujian China
- 6Department of Oncology, Zhangzhou Second Hospital, Zhangzhou, Fujian China
- 7Department of Radiation Oncology, Putian No.95 Hospital, Putian, Fujian China
- 8Department of Radiation Oncology, Quanzhou Binhai Hospital, Quanzhou, Fujian China
Abstract
Pulsed low-dose-rate radiotherapy (PLDR) is a promising reirradiation strategy for refractory solid tumors because of its potential to reduce normal tissue toxicity; however, its immunomodulatory mechanisms remain poorly understood. In this study, we retrospectively analyzed clinical outcomes and treatment-related adverse events in 16 patients with refractory solid tumors treated with PLDR. Using MC38 tumor-bearing mice, we compared PLDR and conventional radiotherapy (cRT) under biologically equivalent dose conditions and performed single-cell RNA sequencing to characterize treatment-associated remodeling of the tumor immune microenvironment (TIM). Multiplex immunofluorescence staining and spatial analysis were further conducted in an independent cohort of 114 patients with rectal cancer to evaluate the clinical relevance of identified immune features. PLDR achieved comparable local tumor control to cRT while reducing treatment-related toxicity and improving overall survival (OS) in mouse models. In the combination-treatment setting, single-cell analyses showed that PLDR + immunotherapy with an anti-PD-1 antibody combined with the targeted agent anlotinib (ITT), compared with cRT + ITT, was associated with enrichment of Gzmk⁺ CD8⁺ T cells, reduced Spp1⁺ tumor-associated macrophages (TAMs) abundance, and altered cell–cell communication between these populations. In our independent rectal cancer cohort, the spatial distance between SPP1⁺ TAMs and GZMK⁺ CD8⁺ T cells was independently associated with OS. These findings suggest that the interaction between SPP1⁺ TAMs and GZMK⁺ CD8⁺ T cells may be closely associated with PLDR-related TIM remodeling and may also serve as a potential prognostic biomarker in rectal cancer.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10565-026-10324-7.
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BibTeX
@article{zhou2026pulsed,
title = {{Pulsed Low-dose-rate Radiotherapy Remodels the Tumor Immune Microenvironment and is Associated With Crosstalk Between SPP1⁺ tumor-associated macrophages and GZMK⁺ CD8⁺ T cells}},
author = {Zihan Zhou and Yafang Hong and Jianhang You and Kaiqian Que and Yiming Lan and Yineng Lin and Junying Peng and Zhenyu Lin and Lanshan Li and Lu Han and Benhua Xu},
journal = {Cell Biology and Toxicology},
year = {2026},
month = nov,
doi = {10.1007/s10565-026-10324-7},
url = {https://doi.org/10.1007/s10565-026-10324-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Pulsed Low-dose-rate Radiotherapy Remodels the Tumor Immune Microenvironment and is Associated With Crosstalk Between SPP1⁺ tumor-associated macrophages and GZMK⁺ CD8⁺ T cells
AU - Zihan Zhou
AU - Yafang Hong
AU - Jianhang You
AU - Kaiqian Que
AU - Yiming Lan
AU - Yineng Lin
AU - Junying Peng
AU - Zhenyu Lin
AU - Lanshan Li
AU - Lu Han
AU - Benhua Xu
PY - 2026
DA - 2026/11/04
JO - Cell Biology and Toxicology
DO - 10.1007/s10565-026-10324-7
UR - https://doi.org/10.1007/s10565-026-10324-7
AB - Pulsed low-dose-rate radiotherapy (PLDR) is a promising reirradiation strategy for refractory solid tumors because of its potential to reduce normal tissue toxicity; however, its immunomodulatory mechanisms remain poorly understood. In this study, we retrospectively analyzed clinical outcomes and treatment-related adverse events in 16 patients with refractory solid tumors treated with PLDR. Using MC38 tumor-bearing mice, we compared PLDR and conventional radiotherapy (cRT) under biologically equivalent dose conditions and performed single-cell RNA sequencing to characterize treatment-associated remodeling of the tumor immune microenvironment (TIM). Multiplex immunofluorescence staining and spatial analysis were further conducted in an independent cohort of 114 patients with rectal cancer to evaluate the clinical relevance of identified immune features. PLDR achieved comparable local tumor control to cRT while reducing treatment-related toxicity and improving overall survival (OS) in mouse models. In the combination-treatment setting, single-cell analyses showed that PLDR + immunotherapy with an anti-PD-1 antibody combined with the targeted agent anlotinib (ITT), compared with cRT + ITT, was associated with enrichment of Gzmk⁺ CD8⁺ T cells, reduced Spp1⁺ tumor-associated macrophages (TAMs) abundance, and altered cell–cell communication between these populations. In our independent rectal cancer cohort, the spatial distance between SPP1⁺ TAMs and GZMK⁺ CD8⁺ T cells was independently associated with OS. These findings suggest that the interaction between SPP1⁺ TAMs and GZMK⁺ CD8⁺ T cells may be closely associated with PLDR-related TIM remodeling and may also serve as a potential prognostic biomarker in rectal cancer. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10565-026-10324-7.
SN - 0742-2091
SN - 1573-6822
ER -