Advances in the Application of Living Cells in Tumor Radiosensitization

Abstract

Radiation therapy (RT) has a critical role in cancer treatment, yet the efficacy is often limited by tumor resistance mechanisms, such as cellular DNA repair activation, heterogeneous cell cycle, hypoxia, and an immunosuppressive microenvironment. Conventional radiosensitization strategies face significant challenges, which are caused by insufficient efficiency, a short treatment window, and off-target toxicities. In contrast, living cells offer a novel strategy to overcome these limitations by leveraging innate characteristics, including tumor chemotaxis and radiosensitization factor secretion. Living cells have recently been applied in radiotherapy to amplify tumor cell killing effects and avoid healthy tissue damage. This review systematically summarizes recent advances in living cell-based radiosensitization strategies, emphasizing the dual roles as tumor targeting carriers and dynamic microenvironment modulators. The radiosensitization mechanisms underlying diverse cell types are analyzed. For example, stem cells enhance radiotherapy via STAT3-mediated DNA repair inhibition, while immune cells and bacteria use immunogenic cell death synergy to induce immune activation. Finally, the challenges and prospects of living cells in achieving radiosensitization are highlighted.

Keywords

Living cells / radiosensitization / tumor microenvironment / tumor radiotherapy / tumor targeting delivery

References

[1] Goldstein M, Kastan MB. The DNA damage response: implications for tumor responses to radiation and chemotherapy. Annu Rev Med 2015; 66: 129-43. [PMID: 25423595 DOI: 10.1146/annurev-med-081313-121208]

[2] Jarosz-Biej M, Smolarczyk R, Cichoń T, Kułach N . Tumor microenvironment as a “Game Changer” in cancer radiotherapy. Int J Mol Sci 2019; 20(13): 3212. [PMID: 31261963 DOI: 10.3390/ijms20133212]

[3] McLaughlin M, Patin EC, Pedersen M, Wilkins A, Dillon MT, et al. Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer 2020; 20(4): 203-17. [PMID: 32161398 DOI: 10.1038/s41568-020-0246-1]

[4] Price JM, Prabhakaran A, West CML. Predicting tumour radiosensitivity to deliver precision radiotherapy. Nat Rev Clin Oncol 2023; 20(2): 83-98. [PMID: 36477705 DOI: 10.1038/s41571-022-00709-y]

[5] Wang H, Mu X, He H, Zhang X-D. Cancer radiosensitizers. Trends Pharmacol Sci 2018; 39(1): 24-48. [PMID: 29224916 DOI: 10.1016/j.tips.2017.11.003]

[6] Higgins GS, O’Cathail SM, Muschel RJ, McKenna WG. Drug radiotherapy combinations: review of previous failures and reasons for future optimism. Cancer Treat Rev 2015; 41(2): 105-13. [PMID: 25579753 DOI: 10.1016/j.ctrv.2014.12.012]

[7] Yu W, Liu R, Zhou Y, Gao H. Size-tunable strategies for a tumor targeted drug delivery system. ACS Cent Sci 2020; 6(2): 100-16. [PMID: 32123729 DOI: 10.1021/acscentsci.9b01139]

[8] Sheibani M, Azizi Y, Shayan M, Nezamoleslami S, Eslami F, et al. Doxorubicin-induced cardiotoxicity: an overview on pre-clinical therapeutic approaches. Cardiovasc Toxicol 2022; 22(4): 292-310. [PMID: 35061218 DOI: 10.1007/s12012-022-09721-1]

[9] Nicolay NH, Lopez Perez R, Debus J, Huber PE. Mesenchymal stem cells - a new hope for radiotherapy-induced tissue damage? Cancer Lett 2015; 366(2): 133-40. [PMID: 26166559 DOI: 10.1016/j.canlet.2015.06.012]

[10] Sadeghzadeh M, Bornehdeli S, Mohahammadrezakhani H, Abolghasemi M, Poursaei E, et al. Dendritic cell therapy in cancer treatment; the state-of-the-art. Life Sci 2020; 254: 117580. [PMID: 32205087 DOI: 10.1016/j.lfs.2020.117580]

[11] Kouhsari E, Ghadimi-Daresajini A, Abdollahi H, Amirmozafari N, Mahdavi SR, et al. The potential roles of bacteria to improve radiation treatment outcome. Clin Transl Oncol 2018; 20(2): 127-39. [PMID: 28623514 DOI: 10.1007/s12094-017-1701-7]

[12] Zhu M, Yang M, Zhang J, Yin Y, Fan X, et al. Immunogenic cell death induction by ionizing radiation. Front Immunol 2021; 12: 705361. [PMID: 34489957 DOI: 10.3389/fimmu.2021.705361]

[13] Xia D, Li J, Feng L, Gao Z, Liu J, et al. Advances in targeting drug biological carriers for enhancing tumor therapy efficacy. Macromol Biosci 2023; 23(12): e2300178. [PMID: 37466216 DOI: 10.1002/mabi.202300178]

[14] Shirvani SM, Huntzinger CJ, Melcher T, Olcott PD, Voronenko Y, et al. Biology-guided radiotherapy: redefining the role of radiotherapy in metastatic cancer. Br J Radiol 2021; 94(1117): 20200873. [PMID: 33112685 DOI: 10.1259/bjr.20200873]

[15] Zhang T, Lin R, Wu H, Jiang X, Gao J. Mesenchymal stem cells: a living carrier for active tumor-targeted delivery. Adv Drug Deliv Rev 2022; 185: 114300. [PMID: 35447165 DOI: 10.1016/j.addr.2022.114300]

[16] Lin Z, Wu Y, Xu Y, Li G, Li Z, et al. Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential. Mol Cancer 2022; 21(1): 179. [PMID: 36100944 DOI: 10.1186/s12943-022-01650-5]

[17] Zhou B, Szymanski CM, Baylink A. Bacterial chemotaxis in human diseases. Trends Microbiol 2023; 31(5): 453-67. [PMID: 36411201 DOI: 10.1016/j.tim.2022.10.007]

[18] Krishnan N, Fang RH, Zhang L. Engineering of stimuli-responsive self-assembled biomimetic nanoparticles. Adv Drug Deliv Rev 2021; 179: 114006. [PMID: 34655662 DOI: 10.1016/j.addr.2021.114006]

[19] Deutsch E, Chargari C, Galluzzi L, Kroemer G. Optimising efficacy and reducing toxicity of anticancer radioimmunotherapy. Lancet Oncol 2019; 20(8): e452-63. [PMID: 31364597 DOI: 10.1016/S1470-2045(19)30171-8]

[20] Huang R-X, Zhou P-K. DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 2020; 5(1): 60. [PMID: 32355263 DOI: 10.1038/s41392-020-0150-x]

[21] Guo S, Yao Y, Tang Y, Xin Z, Wu D, et al. Radiation-induced tumor immune microenvironments and potential targets for combination therapy. Signal Transduct Target Ther 2023; 8(1): 205. [PMID: 37208386 DOI: 10.1038/s41392-023-01462-z]

[22] Wang Y, Liu Z-G, Yuan H, Deng W, Li J, et al. The reciprocity between radiotherapy and cancer immunotherapy. Clin Cancer Res 2019; 25(6): 1709-17. [PMID: 30413527 DOI: 10.1158/1078-0432.CCR-18-2581]

[23] Shi LZ, Bonner JA. Bridging radiotherapy to immunotherapy: the IFN-JAK-STAT axis. Int J Mol Sci 2021; 22(22): 12295. [PMID: 34830176 DOI: 10.3390/ijms222212295]

[24] Wu H-H, Zhou Y, Tabata Y, Gao J-Q. Mesenchymal stem cell-based drug delivery strategy: from cells to biomimetic. J Control Release 2019; 294: 102-13. [PMID: 30553849 DOI: 10.1016/j.jconrel.2018.12.019]

[25] Shah Z, Tian L, Li Z, Jin L, Zhang J, et al. Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer. Cell Stem Cell 2024; 31(6): 803-17.e6. [PMID: 38663406 DOI: 10.1016/j.stem.2024.03.018]

[26] Pauwels B, Wouters A, Peeters M, Vermorken JB, Lardon F. Role of cell cycle perturbations in the combination therapy of chemotherapeutic agents and radiation. Future Oncol 2010; 6(9): 1485-96. [PMID: 20919831 DOI: 10.2217/fon.10.104]

[27] Langroudi L, Jamshidi-Adegani F, Shafiee A, Rad SMAH, Keramati F, et al. MiR-371-373 cluster acts as a tumor-suppressor-miR and promotes cell cycle arrest in unrestricted somatic stem cells. Tumour Biol 2015; 36(10): 7765-74. [PMID: 25941115 DOI: 10.1007/s13277-015-3519-7]

[28] Cheng P-T, Cheng Y-C, Oner M, Li Y-H, Chen M-C, et al. Antrodia salmonea extract inhibits cell proliferation through regulating cell cycle arrest and apoptosis in prostate cancer cell lines. Chin J Physiol 2022; 65(4): 209-14. [PMID: 36073569 DOI: 10.4103/cjp.cjp_78_21]

[29] Heylmann D, Ponath V, Kindler T, Kaina B. Comparison of DNA repair and radiosensitivity of different blood cell populations. Sci Rep 2021; 11(1): 2478. [PMID: 33510180 DOI: 10.1038/s41598-021-81058-1]

[30] Huang Z, Guo H, Lin L, Li S, Yang Y, et al. Application of oncolytic virus in tumor therapy. J Med Virol 2023; 95(4): e28729. [PMID: 37185868 DOI: 10.1002/jmv.28729]

[31] Mei J, Wang R, Xia D, Yang X, Zhou W, et al. BRCA1 is a novel prognostic indicator and associates with immune cell infiltration in hepatocellular carcinoma. DNA Cell Biol 2020; 39(10): 1838-49. [PMID: 32876480 DOI: 10.1089/dna.2020.5644]

[32] Forster JC, Douglass MJJ, Phillips WM, Bezak E. Monte Carlo simulation of the oxygen effect in DNA damage induction by ionizing radiation. Radiat Res 2018; 190(3): 248-61. [PMID: 29953346 DOI: 10.1667/RR15050.1]

[33] Caputo F, De Nicola M, Ghibelli L. Pharmacological potential of bioactive engineered nanomaterials. Biochem Pharmacol 2014; 92(1): 112-30. [PMID: 25175739 DOI: 10.1016/j.bcp.2014.08.015]

[34] Fliervoet LAL, Mastrobattista E. Drug delivery with living cells. Adv Drug Deliv Rev 2016; 106(Pt A): 63-72. [PMID: 27129442 DOI: 10.1016/j.addr.2016.04.021]

[35] Ye M, Liu T, Miao L, Ji H, Xu Z, et al. Cisplatin-encapsulated TRAIL-engineered exosomes from human chorion-derived MSCs for targeted cervical cancer therapy. Stem Cell Res Ther 2024; 15(1): 396. [PMID: 39497209 DOI: 10.1186/s13287-024-04006-6]

[36] Huo M, Wang L, Zhang L, Wei C, Chen Y, et al. Photosynthetic tumor oxygenation by photosensitizer-containing cyanobacteria for enhanced photodynamic therapy. Angew Chem Int Ed Engl 2020; 59(5): 1906-13. [PMID: 31721383 DOI: 10.1002/anie.201912824]

[37] Xing JL, Stea B. Molecular mechanisms of sensitivity and resistance to radiotherapy. Clin Exp Metastasis 2024; 41(4): 517-24. [PMID: 38231337 DOI: 10.1007/s10585-023-10260-4]

[38] Qin Y, You S-H, Zhang Y, Venu A, Hong Y, et al. Genetic programming by nitric oxide-sensing gene switch system in tumor-targeting bacteria. Biosensors (Basel) 2023; 13(2): 266. [PMID: 36832032 DOI: 10.3390/bios13020266]

[39] Bhat SA, Kumar V, Dhanjal DS, Gandhi Y, Mishra SK, et al. Biogenic nanoparticles: pioneering a new era in breast cancer therapeutics-a comprehensive review. Discov Nano 2024; 19(1): 121. [PMID: 39096427 DOI: 10.1186/s11671-024-04072-y]

[40] Dillon MT, Good JS, Harrington KJ. Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol) 2014; 26(5): 257-65. [PMID: 24581946 DOI: 10.1016/j.clon.2014.01.009]

[41] Tian Z, Yu T, Liu J, Wang T, Higuchi A. Introduction to stem cells. Prog Mol Biol Transl Sci 2023; 199: 3-32. [PMID: 37678976 DOI: 10.1016/bs.pmbts.2023.02.012]

[42] Liu W, Cheng G, Cui H, Tian Z, Li B, et al. Theoretical basis, state and challenges of living cell-based drug delivery systems. Theranostics 2024; 14(13): 5152-83. [PMID: 39267776 DOI: 10.7150/thno.99257]

[43] Bianchi ME, Mezzapelle R. The chemokine receptor CXCR4 in cell proliferation and tissue regeneration. Front Immunol 2020; 11: 2109. [PMID: 32983169 DOI: 10.3389/fimmu.2020.02109]

[44] Gopalarethinam J, Nair AP, Iyer M, Vellingiri B, Subramaniam MD. Advantages of mesenchymal stem cell over the other stem cells. Acta Histochem 2023; 125(4): 152041. [PMID: 37167794 DOI: 10.1016/j.acthis.2023.152041]

[45] Sun X, Li K, Zha R, Liu S, Fan Y, et al. Erratum: Preventing tumor progression to the bone by induced tumor-suppressing MSCs: Erratum. Theranostics 2022; 12(14): 6155-6. [PMID: 36168625 DOI: 10.7150/thno.77186]

[46] Yun WS, Shim MK, Lim S, Song S, Kim J, et al. Mesenchymal stem cell-mediated deep tumor delivery of gold nanorod for photothermal therapy. Nanomaterials (Basel) 2022; 12(19): 3410. [PMID: 36234538 DOI: 10.3390/nano12193410]

[47] Xiao J, Zeng L, Ding S, Chen Y, Zhang X, et al. Tumor-tropic adipose-derived mesenchymal stromal cell mediated Bi₂Se₃ nano-radiosensitizers delivery for targeted radiotherapy of non-small cell lung cancer. Adv Healthc Mater 2022; 11(8): e2200143. [PMID: 35195958 DOI: 10.1002/adhm.202200143]

[48] Wang J, Kong D, Zhu L, Wang S, Sun X. Human bone marrow mesenchymal stem cells modified hybrid baculovirus-adeno-associated viral vectors targeting¹³¹I therapy of hypopharyngeal carcinoma. Hum Gene Ther 2020; 31(23-24): 1300-11. [PMID: 32940055 DOI: 10.1089/hum.2020.081]

[49] Sababathy M, Ramanathan G, Tan SC. Targeted delivery of gold nanoparticles by neural stem cells to glioblastoma for enhanced radiation therapy: a review. AIMS Neurosci 2022; 9(3): 303-19. [PMID: 36329899 DOI: 10.3934/Neuroscience.2022017]

[50] Busato F, Khouzai BE, Mognato M. Biological mechanisms to reduce radioresistance and increase the efficacy of radiotherapy: state of the art. Int J Mol Sci 2022; 23(18): 10211. [PMID: 36142122 DOI: 10.3390/ijms231810211]

[51] de Araújo Farias V, O’Valle F, Lerma BA, Ruiz de Almodóvar C, López-Peñalver JJ, et al. Human mesenchymal stem cells enhance the systemic effects of radiotherapy. Oncotarget 2015; 6(31): 31164-80. [PMID: 26378036 DOI: 10.18632/oncotarget.5216]

[52] He N, Kong Y, Lei X, Liu Y, Wang J, et al. MSCs inhibit tumor progression and enhance radiosensitivity of breast cancer cells by down-regulating Stat3 signaling pathway. Cell Death Dis 2018; 9(10): 1026. [PMID: 30297887 DOI: 10.1038/s41419-018-0949-3]

[53] Wu L, Tang Q, Yin X, Yan D, Tang M, et al. The therapeutic potential of adipose tissue-derived mesenchymal stem cells to enhance radiotherapy effects on hepatocellular carcinoma. Front Cell Dev Biol 2019; 7: 267. [PMID: 31781559 DOI: 10.3389/fcell.2019.00267]

[54] Mason KA, Neal R, Hunter N, Ariga H, Ang K, et al. CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors. Radiother Oncol 2006; 80(2): 192-8. [PMID: 16905212 DOI: 10.1016/j.radonc.2006.07.024]

[55] Xia Y, Rao L, Yao H, Wang Z, Ning P, et al. Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater 2020; 32(40): e2002054. [PMID: 32856350 DOI: 10.1002/adma.202002054]

[56] Gaspar N, Zambito G, Löwik CMWG, Mezzanotte L. Active nano-targeting of macrophages. Curr Pharm Des 2019; 25(17): 1951-61. [PMID: 31291874 DOI: 10.2174/1381612825666190710114108]

[57] Sun Z, Chen J, Chen G, Zhang C, Li C. Recent advances of engineered and artificial drug delivery system towards solid tumor based on immune cells. Biomed Mater 2022; 17(2). [PMID: 35042206 DOI: 10.1088/1748-605X/ac4c8b]

[58] Li Z, Huang H, Tang S, Li Y, Yu X-F, et al. Small gold nanorods laden macrophages for enhanced tumor coverage in photothermal therapy. Biomaterials 2016; 74: 144-54. [PMID: 26454052 DOI: 10.1016/j.biomaterials.2015.09.038]

[59] Fu J, Wang D, Mei D, Zhang H, Wang Z, et al. Macrophage mediated biomimetic delivery system for the treatment of lung metastasis of breast cancer. J Control Release 2015; 204: 11-9. [PMID: 25646783 DOI: 10.1016/j.jconrel.2015.01.039]

[60] Zheng W, Ling S, Cao Y, Shao C, Sun X. Combined use of NK cells and radiotherapy in the treatment of solid tumors. Front Immunol 2024; 14: 1306534. [PMID: 38264648 DOI: 10.3389/fimmu.2023.1306534]

[61] Kim K-S, Choi B, Choi H, Ko MJ, Kim D-H, et al. Enhanced natural killer cell anti-tumor activity with nanoparticles mediated ferroptosis and potential therapeutic application in prostate cancer. J Nanobiotechnology 2022; 20(1): 428. [PMID: 36175895 DOI: 10.1186/s12951-022-01635-y]

[62] Zhuang M, Jiang S, Gu A, Chen X, Mingyan E. Radiosensitizing effect of gold nanoparticle loaded with small interfering RNA-SP1 on lung cancer: AuNPs-si-SP1 regulates GZMB for radiosensitivity. Transl Oncol 2021; 14(12): 101210. [PMID: 34517158 DOI: 10.1016/j.tranon.2021.101210]

[63] He J, Yan Y, Zhang J, Wei Z, Li H, et al. Synergistic treatment strategy: combining CAR-NK cell therapy and radiotherapy to combat solid tumors. Front Immunol 2023; 14: 1298683. [PMID: 38162672 DOI: 10.3389/fimmu.2023.1298683]

[64] Xia N, Haopeng P, Gong JU, Lu J, Chen Z, et al. Robo1-specific CAR-NK immunotherapy enhances efficacy of¹²⁵I seed brachytherapy in an orthotopic mouse model of human pancreatic carcinoma. Anticancer Res 2019; 39(11): 5919-25. [PMID: 31704816 DOI: 10.21873/anticanres.13796]

[65] Fan J, Adams A, Sieg N, Heger J-M, Gödel P, et al. Potential synergy between radiotherapy and CAR T-cells - a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy. Radiother Oncol 2023; 183: 109580. [PMID: 36842663 DOI: 10.1016/j.radonc.2023.109580]

[66] Zhou Z, Mai Y, Zhang G, Wang Y, Sun P, et al. Emerging role of immunogenic cell death in cancer immunotherapy: advancing next-generation CAR-T cell immunotherapy by combination. Cancer Lett 2024; 598: 217079. [PMID: 38936505 DOI: 10.1016/j.canlet.2024.217079]

[67] Zhong L, Li Y, Muluh TA, Wang Y. Combination of CAR-T cell therapy and radiotherapy: opportunities and challenges in solid tumors (Review). Oncol Lett 2023; 26(1): 281. [PMID: 37274466 DOI: 10.3892/ol.2023.13867]

[68] Liu S, Yuan S, Liu M, Liu J, Fu S, et al. In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect. Acta Pharm Sin B 2025; 15(1): 627-41. [PMID: 40041911 DOI: 10.1016/j.apsb.2024.08.028]

[69] Arndt C, Loureiro LR, Feldmann A, Jureczek J, Bergmann R, et al. UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells. Oncoimmunology 2020; 9(1): 1743036. [PMID: 32426176 DOI: 10.1080/2162402X.2020.1743036]

[70] Katz SC, Hardaway J, Prince E, Guha P, Cunetta M, et al. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA⁺ liver metastases. Cancer Gene Ther 2020; 27(5): 341-55. [PMID: 31155611 DOI: 10.1038/s41417-019-0104-z]

[71] Qu C, Ping N, Kang L, Liu H, Qin S, et al. Radiation priming chimeric antigen receptor T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma with high tumor burden. J Immunother 2020; 43(1): 32-7. [PMID: 31219975 DOI: 10.1097/CJI.0000000000000284]

[72] Lucas A, Lam D, Cabrales P . Doxorubicin-loaded red blood cells reduced cardiac toxicity and preserved anticancer activity. Drug Deliv 2019; 26(1): 433-42. [PMID: 30929538 DOI: 10.1080/10717544.2019.1591544]

[73] Dong H, Xu X, Wang L, Mo R. Advances in living cell-based anticancer therapeutics. Biomater Sci 2020; 8(9): 2344-65. [PMID: 32254876 DOI: 10.1039/d0bm00036a]

[74] Wang C, Huang J, Zhang Y, Jia H, Chen B. Construction and evaluation of red blood cells-based drug delivery system for chemo-photothermal therapy. Colloids Surf B Biointerfaces 2021; 204: 111789. [PMID: 33932889 DOI: 10.1016/j.colsurfb.2021.111789]

[75] Ahn S, Jung SY, Seo E, Lee SJ. Gold nanoparticle-incorporated human red blood cells (RBCs) for X-ray dynamic imaging. Biomaterials 2011; 32(29): 7191-9. [PMID: 21777977 DOI: 10.1016/j.biomaterials.2011.05.023]

[76] Chiangjong W, Netsirisawan P, Hongeng S, Chutipongtanate S. Red blood cell extracellular vesicle-based drug delivery: challenges and opportunities. Front Med (Lausanne) 2021; 8: 761362. [PMID: 35004730 DOI: 10.3389/fmed.2021.761362]

[77] Siemann DW, Horsman MR. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol Ther 2015; 153: 107-24. [PMID: 26073310 DOI: 10.1016/j.pharmthera.2015.06.006]

[78] Liu T, Shi C, Duan L, Zhang Z, Luo L, et al. A highly hemocompatible erythrocyte membrane-coated ultrasmall selenium nanosystem for simultaneous cancer radiosensitization and precise antiangiogenesis. J Mater Chem B 2018; 6(29): 4756-64. [PMID: 30450208 DOI: 10.1039/C8TB01398E]

[79] Zhou Z, Zhang B, Wang H, Yuan A, Hu Y, et al. Erratum: Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles: Erratum. Theranostics 2020; 10(7): 2943. [PMID: 32194846 DOI: 10.7150/thno.42420]

[80] Xia D, Hang D, Li Y, Jiang W, Zhu J, et al. Au-hemoglobin loaded platelet alleviating tumor hypoxia and enhancing the radiotherapy effect with low-dose X-ray. ACS Nano 2020; 14(11): 15654-68. [PMID: 33108152 DOI: 10.1021/acsnano.0c06541]

[81] Askari S, Goldfinger LE. Roles of miR-223 in platelet function and high on-treatment platelet reactivity: a brief report and review. Genes (Basel) 2025; 16(3): 312. [PMID: 40149463 DOI: 10.3390/genes16030312]

[82] Vass SO, Jarrom D, Wilson WR, Hyde EI, Searle PF. E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954. Br J Cancer 2009; 100(12): 1903-11. [PMID: 19455141 DOI: 10.1038/sj.bjc.6605094]

[83] Liu Y, Niu L, Li N, Wang Y, Liu M, et al. Bacterial-mediated tumor therapy: old treatment in a new context. Adv Sci (Weinh) 2023; 10(12): e2205641. [PMID: 36908053 DOI: 10.1002/advs.202205641]

[84] Wu X, Zhang J, Deng Z, Sun X, Zhang Y, et al. Bacteria-based biohybrids for remodeling adenosine-mediated immunosuppression to boost radiotherapy-triggered antitumor immune response. Biomaterials 2025; 316: 123000. [PMID: 39674101 DOI: 10.1016/j.biomaterials.2024.123000]

[85] Duo Y, Chen Z, Li Z, Li X, Yao Y, et al. Combination of bacterial-targeted delivery of gold-based AIEgen radiosensitizer for fluorescence-image-guided enhanced radio-immunotherapy against advanced cancer. Bioact Mater 2023; 30: 200-13. [PMID: 37663305 DOI: 10.1016/j.bioactmat.2023.05.010]

[86] Huang C, Wang F-B, Liu L, Jiang W, Liu W, et al. Hypoxic tumor radiosensitization using engineered probiotics. Adv Healthc Mater 2021; 10(10): e2002207. [PMID: 33645010 DOI: 10.1002/adhm.202002207]

[87] Liu Z, Lei L, Zhang Z, Du M, Chen Z. Ultrasound-responsive engineered bacteria mediated specific controlled expression of catalase and efficient radiotherapy. Mater Today Bio 2025; 31: 101620. [PMID: 40104641 DOI: 10.1016/j.mtbio.2025.101620]

[88] Lei L, Xu H, Li M, Du M, Chen Z. Dual-pathway tumor radiosensitization strategy based on engineered bacteria capable of targeted delivery of AuNPs and specific hypoxia alleviation. J Nanobiotechnology 2025; 23(1): 254. [PMID: 40155884 DOI: 10.1186/s12951-025-03329-7]

[89] Zhang Y, Liu Y, Li T, Yang X, Lang S, et al. Engineered bacteria breach tumor physical barriers to enhance radio-immunotherapy. J Control Release 2024; 373: 867-78. [PMID: 39097194 DOI: 10.1016/j.jconrel.2024.07.076]

[90] Shi J, Ma Z, Pan H, Liu Y, Chu Y, Wang J. Biofilm-encapsulated nano drug delivery system for the treatment of colon cancer. J Microencapsul 2020; 37(7): 481-491. [PMID: 32700606 DOI: 10.1080/02652048.2020.1797914]

[91] Pan P, Dong X, Chen Y, Zeng X, Zhang X-Z. Engineered bacteria for enhanced radiotherapy against breast carcinoma. ACS Nano 2022; 16(1): 801-12. [PMID: 35029367 DOI: 10.1021/acsnano.1c08350]

[92] Zhang Y, Huang R, Jiang Y, Shen W, Pei H, et al. The role of bacteria and its derived biomaterials in cancer radiotherapy. Acta Pharm Sin B 2023; 13(10): 4149-71. [PMID: 37799393 DOI: 10.1016/j.apsb.2022.10.013]

[93] Milas L, Mason KA, Ariga H, Hunter N, Neal R, et al. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res 2004; 64(15): 5074-7. [PMID: 15289307 DOI: 10.1158/0008-5472.CAN-04-0926]

[94] Mason KA, Ariga H, Neal R, Valdecanas D, Hunter N, et al. Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances tumor response to fractionated radiotherapy. Clin Cancer Res 2005; 11(1): 361-9. [PMID: 15671567]

[95] Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 1995; 374(6522): 546-9. [PMID: 7700380 DOI: 10.1038/374546a0]

[96] Prack Mc Cormick B, Belgorosky D, Langle Y, Balarino N, Sandes E, et al. Bacillus Calmette-Guerin improves local and systemic response to radiotherapy in invasive bladder cancer. Nitric Oxide 2017; 64: 22-30. [PMID: 28126499 DOI: 10.1016/j.niox.2017.01.008]

[97] Yang J, Wu Z, Chen Y, Hu C, Li D, et al. Pre-treatment with Bifidobacterium infantis and its specific antibodies enhance targeted radiosensitization in a murine model for lung cancer. J Cancer Res Clin Oncol 2021; 147(2): 411-22. [PMID: 33130941 DOI: 10.1007/s00432-020-03434-0]

[98] Wang W, Zheng Y, Wu Z, Wu M, Chen Y, et al. Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy. J Transl Med 2024; 22(1): 657. [PMID: 39010088 DOI: 10.1186/s12967-024-05469-0]

[99] Li X, Wang H, Li Z, Tao F, Wu J, et al. Oxygen switches: refueling for cancer radiotherapy. Front Oncol 2023; 12: 1085432. [PMID: 36873299 DOI: 10.3389/fonc.2022.1085432]

[100] Qiao Y, Yang F, Xie T, Du Z, Zhong D, et al. Engineered algae: a novel oxygen-generating system for effective treatment of hypoxic cancer. Sci Adv 2020; 6(21): eaba5996. [PMID: 32490207 DOI: 10.1126/sciadv.aba5996]

[101] Li W, Zhong D, Hua S, Du Z, Zhou M. Biomineralized biohybrid algae for tumor hypoxia modulation and cascade radio-photodynamic therapy. ACS Appl Mater Interfaces 2020; 12(40): 44541-53. [PMID: 32935973 DOI: 10.1021/acsami.0c14400]

[102] Chai R, Yu L, Dong C, Yin Y, Wang S, et al. Oxygen-evolving photosynthetic cyanobacteria for 2D bismuthene radiosensitizer-enhanced cancer radiotherapy. Bioact Mater 2022; 17: 276-88. [PMID: 35386463 DOI: 10.1016/j.bioactmat.2022.01.014]

[103] Hua S, Zhao J, Li L, Liu C, Zhou L, et al. Photosynthetic bacteria-based whole-cell inorganic-biohybrid system for multimodal enhanced tumor radiotherapy. J Nanobiotechnology 2024; 22(1): 379. [PMID: 38943158 DOI: 10.1186/s12951-024-02654-7]

[104] Kosoglu MA, Hood RL, Rossmeisl JH Jr, Grant DC, Xu Y, et al. Fiberoptic microneedles: novel optical diffusers for interstitial delivery of therapeutic light. Lasers Surg Med 2011; 43(9): 914-20. [PMID: 22006734 DOI: 10.1002/lsm.21129]

[105] Liang K, Liu Q, Li P, Luo H, Wang H, Kong Q. Genetically engineered Salmonella Typhimurium: recent advances in cancer therapy. Cancer Lett 2019; 448: 168-81. [PMID: 30753837 DOI: 10.1016/j.canlet.2019.01.037]

[106] Alonso-Roman R, Mosig AS, Figge MT, Papenfort K, Eggeling C, et al. Organ-on-chip models for infectious disease research. Nat Microbiol 2024; 9(4): 891-904. [PMID: 38528150 DOI: 10.1038/s41564-024-01645-6]

[107] Branco F, Cunha J, Mendes M, Sousa JJ, Vitorino C. 3D Bioprinting models for glioblastoma: from scaffold design to therapeutic application. Adv Mater 2025; 37(18): e2501994. [PMID: 40116532 DOI: 10.1002/adma.202501994]

[108] Nie M, Shima A, Yamamoto M, Takeuchi S. Scalable tissue biofabrication via perfusable hollow fiber arrays for cultured meat applications. Trends Biotechnol 2025; 43(8): 1938-60. [PMID: 40246628 DOI: 10.1016/j.tibtech.2025.02.022]

[109] Ishag HZA, Xiong Q, Liu M, Feng Z, Shao G. E. coli recA gene improves gene targeted homologous recombination in Mycoplasma hyorhinis. J Microbiol Methods 2017; 136: 49-56. [PMID: 28285864 DOI: 10.1016/j.mimet.2017.03.004]

[110] Abrams K, Aiuti A, Eichler H-G, Ziegler A . Considerations driving the choice in clinical trial design of cell and gene therapy products: weighing convenience versus necessity. Cytotherapy 2025;S1465-3249(25)00738-8. [PMID: 40542809 DOI: 10.1016/j.jcyt.2025.06.001]