Mapping the research landscape of the correlation between radiotherapy and tumor immune microenvironment: A bibliometric analysis

Abstract

Background: Radiation therapy (RT) is a cornerstone of cancer treatment that not only directly kills tumor cells but also produces synergistic effects with immunotherapy by remodeling the tumor immune microenvironment (TIME). However, systematic bibliometric analyses of RT-TIME interactions remain unexplored.

Methods: This study analyzed all the literature related to RT and TIME from the Web of Science (WOS) Core Collection through 2024. It utilized R, VOSviewer, and CiteSpace to visually analyze authors, countries, institutions, keywords, co-cited references, research hotspots, and frontiers.

Results: China, the United States, and Germany emerged as the leading contributors, with 1,253, 581, and 162 publications, respectively. Frontiers in Immunology was the most active journal (n = 186). Co-occurrence analysis identified “radiotherapy” (n = 898) and “immunotherapy” (n = 895) as core themes, with sustained focus on “CD8(+) T cells” (citation burst = 8.81) and emerging interest in “(nature killer) NK cells.” Temporal evolution revealed three research phases: initial exploration (2007–2015) of RT's immunomodulatory mechanisms of RT, clinical validation of RT combined with Programmed Cell Death Protein 1 (PD-1)/ Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) inhibitors (2015–2020), and recent diversification (2020–2024) toward technical optimization (e.g., stereotactic RT), tumor type expansion, and safety management.

Conclusions: This comprehensive bibliometric analysis highlights future priorities, including exploring optimal synergistic strategies for combination therapies, investigating spatiotemporally resolved immune mechanisms, and developing predictive biomarkers. These areas are currently experiencing rapid growth and require further research.

Keywords

bibliometrics / citespace / immunotherapy / tumor immune microenvironment / radiotherapy

References

[1] Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020; 20(11): 651-668.

[2] Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer. 2004; 4(9): 737-747.

[3] Scala S. Molecular Pathways: Targeting the CXCR4-CXCL12 Axis–Untapped Potential in the Tumor Microenvironment. Clin Cancer Res. 2015; 21(19): 4278-4285.

[4] Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018; 24(5): 541-550.

[5] Meng K, Lu H. Clinical application of high-LET radiotherapy combined with immunotherapy in malignant tumors. Precis Radiat Oncol. 2024; 8(1): 42-46.

[6] Liu Y, Jiang X, Wu Y, Yu H. Global research landscape and trends of cancer radiotherapy plus immunotherapy: A bibliometric analysis. Heliyon. 2024; 10(5):e27103.

[7] Hicks D, Wouters P, Waltman L, de Rijcke S, Rafols I. Bibliometrics: The Leiden Manifesto for research metrics. Nature. 2015; 520(7548): 429-431.

[8] Jiang M, Qi Y, Liu H, Chen Y. The Role of Nanomaterials and Nanotechnologies in Wastewater Treatment: a Bibliometric Analysis. Nanoscale Res Lett. 2018; 13(1): 233.

[9] Grunsky EC, R: a data analysis and statistical programming environment - an emerging tool for the geosciences. Comput. Geosciences. 2002; 28(10): 1219-1222.

[10] Aria M. Cuccurullo C. bibliometrix: An R-tool for comprehensive science mapping analysis. J Informetr. 2017; 11(4): 959–975.

[11] van Eck NJ, Waltman L. Software survey: VOSviewer, a computer program for bibliometric mapping. Scientometrics. 2010; 84(2): 523-538.

[12] Chen C. Searching for intellectual turning points: progressive knowledge domain visualization. Proc Natl Acad Sci U S A. 2004; 101 Suppl 1(Suppl 1): 5303-5310.

[13] Freeman LC. Centrality in social networks conceptual clarificationCentrality in social networks conceptual clarification. Soc Netw. 1979; 1(3): 215–239.

[14] Kleinberg J. Bursty and hierarchical structure in streams. Data Min Knowl Discov. 2003; 7(4): 373-397.

[15] Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014; 124(2): 687-695.

[16] Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004; 58(3): 862-870.

[17] Hellström KE, Hellström I, Kant JA, Tamerius JD. Regression and inhibition of sarcoma growth by interference with a radiosensitive T-cell population. J Exp Med. 1978; 148(3): 799-804.

[18] Lee Y, Auh SL, Wang Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009; 114(3): 589-595.

[19] North RJ. Radiation-induced, immunologically mediated regression of an established tumor as an example of successful therapeutic immunomanipulation. Preferential elimination of suppressor T cells allows sustained production of effector T cells. J Exp Med. 1986; 164(5): 1652-1666.

[20] Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison?. Nat Rev Clin Oncol. 2017; 14(6): 365-379.

[21] Zhang B, Bowerman NA, Salama JK, et al. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med. 2007; 204(1): 49-55.

[22] Meng K, Lu H. Clinical application of high-LET radiotherapy combined with immunotherapy in malignant tumors. Precis Radiat Oncol. 2024; 8(1): 42-46.

[23] Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007; 13(9): 1050-1059.

[24] Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012; 12(12): 860-875.

[25] Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006; 203(5): 1259-1271.

[26] Zhang L, Xu Y, Shen J, et al. Feasibility study of DCs/CIKs combined with thoracic radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Radiat Oncol. 2016; 11: 60.

[27] Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011; 331(6013): 44-49.

[28] Bejarano L, Kauzlaric A, Lamprou E, et al. Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms. Cancer Cell. 2024; 42(3):378-395.e 10.

[29] Romani L, Bistoni F, Perruccio K, et al. Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance. Blood. 2006; 108(7): 2265-2274.

[30] Wang Z, Tang Y, Tan Y, Wei Q, Yu W. Cancer-associated fibroblasts in radiotherapy: challenges and new opportunities. Cell Commun Signal. 2019; 17(1): 47.

[31] Whiteside SK, Grant FM, Alvisi G, et al. Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion. Sci Immunol. 2023; 8(90):eabo5558.

[32] Ziani L, Chouaib S, Thiery J. Alteration of the Antitumor Immune Response by Cancer-Associated Fibroblasts. Front Immunol. 2018; 9: 414.

[33] Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009; 15(17): 5379-5388.

[34] Gong Y, Cheng Y, Zeng F, et al. A self-gelling hemostatic powder boosting radiotherapy-elicited NK cell immunity to combat postoperative hepatocellular carcinoma relapse. Biomaterials. 2025; 317:123068.

[35] Luo R, Yu M, Wu Y, et al. The Eclipse-Radiotherapy Combined with ICI Orchestrates CD8+T Cell- and NK Cell-Dependent Anti-Tumor Efficacy against Bulky Tumors. Int J Radiat Oncol Biol Phys. 2024. 120(2): S95-S95.

[36] Walle T, Kraske JA, Liao B, et al. Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8. Sci Adv. 2022; 8(12):eabh4050.

RIGHTS & PERMISSIONS

2026 The Author(s). Precision Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Shandong Cancer Hospital & Institute.