“Reinforcement” by Tumor Microenvironment: The Seventh “R” of Radiobiology

Radiation therapy is a highly effective method for inhibiting tumor growth and is widely used in clinical settings. 1 Allen C Her S Jaffray DA Radiotherapy for cancer: Present and future. Adv Drug Deliv Rev. 2017; 109: 1-2 Crossref PubMed Scopus (114) Google Scholar It damages the vital biomolecules (especially DNA) of cancer cells and eventually promotes them to different cellular death processes, including apoptosis, necrosis, and necroptosis, among others. 2 Chen H Han Z Luo Q et al. Radiotherapy modulates tumor cell fate decisions: A review. Radiat Oncol. 2022; 17: 196 Crossref Scopus (7) Google Scholar Meanwhile, a fraction of cancer cells exhibit resistance against the radiation effects. 3 Wu Y Song Y Wang R Wang T Molecular mechanisms of tumor resistance to radiotherapy. Mole Cancer. 2023; 22: 96 Crossref Scopus (7) Google Scholar Despite extensive advances, radioresistance remains the main challenge hindering the effectiveness of radiation therapy. 4 de Mey S Dufait I De Ridder M Radioresistance of human cancers: Clinical implications of genetic expression signatures. Front Oncol. 2021; 11761901 Crossref Scopus (7) Google Scholar To date, the determinant factors of response to radiation have been presented as 6 terms that start with the letter R, including Regeneration (proliferation rate), Repair (DNA damage repair efficacy), Reoxygenation (rate of oxygen pressure in tumor tissue), Redistribution (cell cycle stage), Radiosensitivity (intrinsic radiosensitivity of cancer cells), and Reactivation (immune response after radiation). In 1975, Rodney H. Withers put forward the first 4 “Rs” of radiobiology, which influence the outcome of fractionated radiation therapy in terms of tumor control and normal tissue sparing. 5 Withers HR The four R's of radiotherapy. in: Lett JT Adler H Advances in Radiation Biology. 5. Elsevier, 1975: 241-271 Google Scholar In 1989, Steel et al introduced the fifth R of radiobiology (intrinsic Radiosensitivity) by observing different steepness of survival curves of different cancer cell lines in response to a single 2 Gy fraction. 6 Steel GG McMillan TJ Peacock JH The 5Rs of radiobiology. Int J Radiat Biol. 1989; 56: 1045-1048 Crossref PubMed Scopus (189) Google Scholar In 2019, Boustani et al considered “immune Reactivation” as the sixth R of radiobiology. They outlined how tumor response to radiation can be influenced by antitumor immune reaction. 7 Boustani J Grapin M Laurent PA Apetoh L Mirjolet C The 6th R of radiobiology: Reactivation of anti-tumor immune response. Cancers (Basel). 2019; 11: 860 Crossref PubMed Scopus (64) Google Scholar This interplay is the basis of combining radiation therapy with various types of immunotherapy, particularly immune checkpoint inhibitors. 8 Zhang Z Liu X Chen D Yu J Radiotherapy combined with immunotherapy: The dawn of cancer treatment. Signal Transduct Target Ther. 2022; 7: 258 Crossref PubMed Scopus (89) Google Scholar