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X-ray activated platinum complex induces DNA damage and enhances cancer immunotherapy through abscopal effect

Nature Biomedical Engineering (2026)Cite this article

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Abstract

Radiotherapy is used in more than half of cancer patients, yet most radiosensitizers increase reactive oxygen species (ROS) to enhance cytotoxicity in treated cells. This approach has limited use in hypoxic tumours and may cause oxidative injury to healthy tissues. We developed a platinum(II) azido complex (Complex 1) that releases platinonitrene upon X-ray exposure. Platinonitrene reacts with nucleophilic sites on DNA bases, forming covalent adducts that disrupt DNA integrity and cause double-strand breaks, leading to tumour cell death through a mechanism distinct from classical platinum coordination. Computational modelling elucidated this pathway and supported its role in radiosensitization. Complex 1 was synthesized by sequential ligand exchange of potassium tetrachloroplatinate with cyclohexanediamine, silver nitrate and sodium azide. In murine models, complex 1 showed negligible toxicity to major organs and normal immune cells while selectively reducing regulatory T-cell infiltration in tumours. Combined with low-dose radiotherapy and programmed cell death protein 1 blockade, it achieved complete regression of bilateral tumours in 40% of mice, demonstrating a strong abscopal effect. This work establishes metallonitrene-based, ROS-independent radiosensitization for precision radiotherapy.

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Fig. 1: Generation of platinonitrene with complex 1 upon RT and its DNA platination via N-N coupling.
Fig. 2: Complex 1-sensitized RT induces enhanced cytotoxicity, exhibits stronger DNA damage and induces more robust immunogenic cell death in CT26 cells.
Fig. 3: Complex 1-sensitized RT effectively inhibits the growth of established CT26 tumours.
Fig. 4: RNA-seq of CT26 tumour tissues suggests that complex 1-sensitized RT induced immune cell infiltration into the TME.
Fig. 5: Complex 1 itself could inhibit Treg cell proliferation.
Fig. 6: Complex 1-sensitized RT enhances immunotherapy and the abscopal effect on syngeneic CT26 tumour model.
Fig. 7: Complex 1-sensitized RT has reliable biosecurity and derives long-lasting immune memory effect on syngeneic CT26 tumour model.

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Data availability

All relevant data supporting the results in this study are available within the paper. The raw and analysed datasets generated during the study are available for academic purposes from the corresponding authors upon request. RNA sequencing data that support the findings of this study are deposited and made publicly available in the NCBI Gene Expression Omnibus repository under accession number GSE314315. Source data are provided with this paper.

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Acknowledgements

This work was supported by: the National Natural Science Foundation of China (32271433, 32471437 and 31971299); 2025IHM01180, Start-Up grants KY2060000124 and KJ2060190030 from the University of Science and Technology of China and Fundamental Research Funds for the Central Universities (YD9100002031, WK2060190101) to Y.M. ; the National Natural Science Foundation of China (22422306) and National Key R&D Program of China (2024YFA1509203) to S.X.; the Natural Science Foundation of Anhui Province (2208085J48) and Hefei Comprehensive National Science Center Institute of Health and Medicine Project (DJK-LX-2022006, 2023IHM01044) to B.L.; the National Key R&D Program of China (2022YFA1303200) to K.Q, and the National Natural Science Foundation of China grants (T2125012 and 92574202) and Strategic Priority Research Program of Chinese Academy of Sciences (XDB0940301) to K.Q.; funding from the Global STEM Professorship, start-up fund (Grant No. 2023-Xing, HKPU), and Projects of RISA PolyU (UGC) (1-CDN9) to B.X. The work described in this paper was also partially supported by a grant from the NSFC/RGC Joint Research Scheme sponsored by the Research Grants Council of Hong Kong and the National Natural Science Foundation of China (Project No. N_PolyU521/25) to B.X.; and by the Fundamental Research Funds for the Central Universities (WK2060000099) to Y.X. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine; Hefei National Research Center for Physical Sciences at the Microscale; Department of Chemistry, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Guiyuan Chen, Xiangxia Li, Kecheng Wu, Qilong Zhu, Changqing Guo, Huanjun Zhu, Ruike Dai, Ying He & Yuanzeng Min

  2. Key Laboratory of Precision and Intelligent Chemistry, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Yu Huang & Shiyan Xiao

  3. School of Physical Sciences and Ion Medical Research Institute, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Cheng Zheng & Yidong Yang

  4. Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Haopeng Fang, Qiaoyun Zhang & Bofeng Li

  5. Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Ke Liu & Kun Qu

  6. Intelligent Pathology Institute, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Qiuhong Zhu & Wenchao Zhou

  7. Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Zibo Li

  8. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Shaomin Tian

  9. School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore

    Bengang Xing

  10. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China

    Bengang Xing

  11. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  12. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  13. Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Xiaoyuan Chen

  14. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), Proteos, Singapore, Singapore

    Xiaoyuan Chen

  15. Department of Radiation Oncology, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

    Andrew Z. Wang

  16. School of Chemistry and Materials Science, Experimental Center of Engineering and Material Sciences, School of Engineering Science, University of Science and Technology of China, Hefei, Anhui, P. R. China

    Yujie Xiong

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  1. Guiyuan Chen
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Contributions

Y.M. conceived and designed the experiments with G.C. G.C. and X.L. performed the efficacy study. G.C. also performed the mechanistic study. Y. Huang and S.X. performed the calculations. C.Z., G.C., C.G. and H.Z. conducted radiotherapy for in vitro and in vivo experiments. G.C., H.F., Q. Zhang and B.L. designed and performed the flow cytometry analysis of Treg cells. G.C., K.L. and K.Q. performed the analysis of RNA sequencing. K.W., Qilong Zhu, R.D. and Y. He helped to perform the experiments at cellular level. Qiuhong Zhu and W.Z. helped to establish the glioblastoma model. G.C. and Y.M. wrote the manuscript. All authors analysed and discussed the data, revised the manuscript, and approved the submission.

Corresponding authors

Correspondence to Kun Qu, Bofeng Li, Shiyan Xiao or Yuanzeng Min.

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Extended data

Extended Data Fig. 1 Characteristic NLMOs resulting from NBO analysis support the platinonitrene description of complex 2 and 3.

a, Structural representation of 1. b, N2 releases from 1 under X-ray irradiation, and produces metallonitrene compound 2 and 3. c, Scan of the Nα-Nβ bond length for singlet and triplet states of 1 to illustrate the interplay of singlet and triplet states during the loss of N2 from the molecule of 1. The triplet state of complex 2 is strongly stabilized by 12.7 kcal/mol compared with its singlet state. The calculations were performed at the level of PBE0-D/def2-TZVPP, and the step size during the scan is set to 0.01 Å. d-g, Characteristic NLMOs resulting from an NBO analysis. d-e, Pt-N σ-bond, singly occupied py, pz orbitals and s-type lone pair localized at N atom (d), and Pt-centred and doubly occupied d orbitals (e) of 2, which has only one nitrene group. f-g, Pt-N σ-bond, singly occupied py, pz orbitals and s-type lone pair localized at N atom (f), and Pt-centred and doubly occupied d orbitals (g) of 3, which has two nitrene groups. d to g show that the covalent Pt-N σ-bonds polarized towards nitrogen, a s-type lone pair and two singly occupied p-type NLMOs on the nitrene N atom as well as four essentially nonbonding Pt d orbitals which shared only insignificant N contributions (Pt-N Mayer bond order: 1.15 for 2 and 1.06 for 3).

Extended Data Fig. 2 Complex 1 sensitized RT effectively inhibits the growth and metastasis of 4T1 tumours.

a, Schemes of 4T1 tumour inoculation and therapies. b, Tumour growth curves of each mouse. c, Average tumour growth curves showed 1 sensitized RT effectively inhibited the growth of 4T1 tumours (n = 9). Tumour growth with the passage of time was compared by two-way ANOVA (Tukey’s test). d, Survival curves showed 1 sensitized RT prolonged the survival time of mice (n = 9). Differences in survival were determined for each group by the Kaplan-Meier method, and the overall P value was calculated by the log-rank test. e, Representative lung pathology sections of mice showed that 1 sensitized RT effectively inhibited lung metastasis of 4T1 tumours. Black arrow, pulmonary nodules. f, Lung metastasis count of mice (n = 3). One-way ANOVA multiple comparisons (Tukey’s multiple comparisons test) were used when more than two groups were compared. All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Fig. 3 cis-Pt(NH3)2(N3)2 sensitized RT effectively inhibits the growth of established CT26 tumours.

a, Schemes of CT26 tumour inoculation and therapies. b, Tumour growth curves of each mouse. c, Average tumour growth curves showed cis-Pt(NH3)2(N3)2 sensitized RT effectively inhibited the growth of established CT26 tumours (n = 6). Tumour growth with the passage of time was compared by two-way ANOVA (Tukey’s test). d, Survival curves showed cis-Pt(NH3)2(N3)2 sensitized RT prolonged the survival time of mice (n = 6). Differences in survival were determined for each group by the Kaplan–Meier method, and the overall P value was calculated by the log-rank test. All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Fig. 4 Complex 1 sensitized RT enhances abscopal effect on syngeneic CT26 tumour model.

a, Schemes of primary and secondary tumour inoculation and therapies. b, Primary and secondary tumour growth curves of each mouse showed 1 in combination with RT and αPD-1 suppress growth of bilateral tumours. c, Average primary tumour growth curves of each group (n = 8). d, Average secondary tumour growth curves of each group (n = 8). Tumour growth with the passage of time was compared by two-way ANOVA (Tukey’s test). e, Survival curves showed 1 in combination with RT and αPD-1 prolonged survival time of mice in bilateral tumour model (n = 8). Differences in survival were determined for each group by the Kaplan–Meier method, and the overall P value was calculated by the log-rank test. f, Body weight change curve of mice (n = 8). All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Fig. 5 Flow analysis of 1 sensitized RT enhancing immunotherapy and abscopal effect.

a, Quantification of DCs maturation in TDLNs by flow cytometry indicated 1 sensitized RT enhancing abscopal effect (Blank and RT + αPD-1, n = 4; 1 + RT + αPD-1, n = 3). b, Corresponding representative flow plots showed DCs in TDLNs. c, Image of representative primary and secondary tumours. d, Representative flow plots of primary and secondary tumour infiltrating CD45+CD3+, CD8+and Treg (CD4+Foxp3+) cells. One-way ANOVA multiple comparisons (Tukey’s multiple comparisons test) were used when more than two groups were compared. All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Fig. 6 Platinonitrene-based radiosensitizer enhances abscopal effect that is superior to that of oxaliplatin and has reliable security.

a-b, Average primary and secondary tumour growth curves showed 1 in combination with low dose of RT and αPD-1 suppress growth of bilateral tumours (n = 10). Tumour growth with the passage of time was compared by two-way ANOVA (Tukey’s test). c, Representative TUNEL (TdT-mediated dUTP nick end labelling) and H&E (Haematoxylin and Eosin staining) section of kidneys showed 1 in combination with low dose of RT and αPD-1 would not cause the damage of kidney. d-h, Analysis of BUN, CRE, TBil (total bilirubin), ALT (alanine transaminase) and AST (aspartate aminotransferase) in serum showed 1 held a better biosecurity than oxaliplatin in combination with immunotherapy (n = 10). i, Representative TUNEL and H&E section of livers showed 1 in combination with low dose of RT and αPD-1 would not cause the damage of livers. One-way ANOVA was used for multiple comparisons (Tukey’s multiple comparisons test) when more than two groups were compared. All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Fig. 7 Complex 1 sensitized RT effectively inhibits the growth of orthotopic glioblastoma.

a, Schemes of orthotopic glioblastoma inoculation and therapies. b, Bioluminescence imaging suggested complex 1 sensitized RT effectively inhibited the growth of orthotopic glioblastoma (n = 8). c, Changes of bioluminescence counts of brain tumour area of each mouse (n = 8). d, Body weight change curve of each mouse (n = 8). e, Average bioluminescence counts change curves showed 1 sensitized RT effectively inhibited the growth of orthotopic glioblastoma (n = 8). f, Average body weight change curve suggested mice in 1 + RT group had the slowest weight loss (n = 8). g, Survival curves showed 1 sensitized RT significantly prolonged survival time of mice in orthotopic glioblastoma model (n = 8). Average bioluminescence counts change with the passage of time was compared by two-way ANOVA (Tukey’s test). Differences in survival were determined for each group by the Kaplan–Meier method, and the overall P value was calculated by the log-rank test. f, Body weight change curve of mice (n = 8). All the values in the present study are presented as the mean ± s.d., and all replicates are biological independent samples.

Source data

Extended Data Table 1 Parameters of bonded interactions for Platinum coordinated species of 1. Details of the atom labels can be found in Extended Data Fig. 1
Full size table

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Chen, G., Li, X., Huang, Y. et al. X-ray activated platinum complex induces DNA damage and enhances cancer immunotherapy through abscopal effect. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01612-y

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