Advances in Engineered Nano-sensitizers for Chemoradiotherapy of Cancer: Overcoming Microenvironmental Barriers

Zi-Yan Zheng; Dan-Hua Zhou; Zhi-Hua Gan; Qing-Song Yu

doi:10.1007/s10118-026-3748-9

Your Location：

Home >

Browse articles >

Advances in Engineered Nano-sensitizers for Chemoradiotherapy of Cancer: Overcoming Microenvironmental Barriers

REVIEW | Updated：2026-08-05

- Advances in Engineered Nano-sensitizers for Chemoradiotherapy of Cancer: Overcoming Microenvironmental Barriers
- Chinese Journal of Polymer Science Vol. 44, Pages: 1-22(2026)
- Affiliations：
  
  a.The State Key Laboratory of Organic−Inorganic Composites, Beijing Laboratory of Biomedical Materials, Key Laboratory of Biomedical Materials of Natural Macromolecules (Ministry of Education), College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China
  b.Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM), Xiamen 361005, China
- Author bio：
  
  zhoudh@xmu.edu.cn (D.H.Z.)
  yuqs@mail.buct.edu.cn (Q.S.Y.)
- Funds：
- DOI：10.1007/s10118-026-3748-9
  CLC：
- Received：23 March 2026，
  
  Accepted：15 May 2026，
  
  Online First：05 August 2026，
  
  Published：2026-06
- Accepted：
Scan QR Code
Zheng, Z. Y.; Zhou, D. H.; Gan, Z. H.; Yu, Q. S. Advances in engineered nano-sensitizers for chemoradiotherapy of cancer: overcoming microenvironmental barriers. Chinese J. Polym. Sci. https://doi.org/10.1007/s10118-026-3748-9

Zi-Yan Zheng, Dan-Hua Zhou, Zhi-Hua Gan, et al. Advances in Engineered Nano-sensitizers for Chemoradiotherapy of Cancer: Overcoming Microenvironmental Barriers[J/OL]. Chinese Journal of Polymer Science, 2026, 441-22.
Zheng, Z. Y.; Zhou, D. H.; Gan, Z. H.; Yu, Q. S. Advances in engineered nano-sensitizers for chemoradiotherapy of cancer: overcoming microenvironmental barriers. Chinese J. Polym. Sci. https://doi.org/10.1007/s10118-026-3748-9 DOI：

Zi-Yan Zheng, Dan-Hua Zhou, Zhi-Hua Gan, et al. Advances in Engineered Nano-sensitizers for Chemoradiotherapy of Cancer: Overcoming Microenvironmental Barriers[J/OL]. Chinese Journal of Polymer Science, 2026, 441-22. DOI： 10.1007/s10118-026-3748-9.

摘要

Abstract

Conventional chemotherapy and radiotherapy damage normal tissues due to off-target toxicity

impairing patient prognosis. Chemoradiotherapy (CRT)—the concurrent use of chemotherapy and radiotherapy—has gained considerable attention

as it suppresses primary tumors and reduces metastasis. However

dose-limiting drug toxicity remains a major barrier to clinical CRT. To mitigate adverse effects and improve drug bioavailability

nano-sensitizer (NS)-mediated CRT has become a research focus. Nonetheless

unique tumor microenvironmental features

including hypoxia

abnormal vasculature

elevated reactive oxygen species

mild acidity

dense extracellular matrix

and immunosuppression

severely compromise NS efficacy. Accordingly

smart NS designed to surmount these microenvironmental barriers represent a key direction in drug development. This review summarizes recent advances in tumor microenvironment-targeted NS and their preclinical and clinical applications

aiming to deepen understanding of microenvironmental challenges in CRT and facilitate the development of potent NS.

关键词

Keywords

references

Sutkowy, P.; Czeleń, P. Redox balance in cancer in the context of tumor prevention and treatment. Biomedicines 2025 , 13 , 1149..

[Naka bayashi, N.; Hirose, M.; Suzuki, R.; Suzumiya, J.; Igawa, M. How asymptomatic are early cancer patients of five organs based on registry data in Japan. Int. J. Clin. Oncol . 2018 , 23 , 999−1006..

Mun, E. J.; Babiker, H. M.; Weinberg, U.; Kirson, E. D.; Von Hoff, D. D. Tumor-treating fields: a fourth modality in cancer treatment. Clin. Cancer. Res. 2018 , 24 , 266−275..

Rallis, K. S.; Yau, T. H. L.; Sideris, M. Chemoradiotherapy in cancer treatment: rationale and clinical applications. Anticancer Res. 2021 , 41 , 1−7..

Lawrence, T. S.; Haffty, B. G.; Harris, J. R. Milestones in the use of combined-modality radiation therapy and chemotherapy. J. Clin. Oncol. 2014 , 32 , 1173−1179..

Seiwert, T. Y.; Salama, J. K.; Vokes, E. E. The concurrent chemoradiation paradigm—general principles. Nat. Clin. Pract. Oncol. 2007 , 4 , 86−100..

Nishimura, Y. Rationale for chemoradiotherapy. Int. J. Clin. Oncol. 2004 , 9 , 414−420..

McRee, A. J.; Cowherd, S.; Wang, A. Z.; Goldberg, R. M. Chemoradiation therapy in the management of gastrointestinal malignancies. Future Oncol. 2011 , 7 , 409−426..

Kaur, S.; Prasad, C.; Balakrishnan, B.; Banerjee, R. Trigger responsive polymeric nanocarriers for cancer therapy. Biomater. Sci. 2015 , 3 , 955−987..

Caster, J. M.; Wang, A. Z. Applying nanotherapeutics to improve chemoradiotherapy treatment for cancer. Ther. Deliv. 2017 , 8 , 791−803..

Sun, H.; Wang, X.; Zhai, S. The Rational Design and Biological Mechanisms of Nanoradiosensitizers. Nanomaterials 2020 , 10 , 504..

Shi, Y.; van der Meel, R.; Chen, X.; Lammers, T. The EPR effect and beyond: strategies to improve tumor targeting and cancer nanomedicine treatment efficacy. Theranostics 2020 , 10 , 7921−7924..

Pan, Y.; Liu, L.; Mou, X.; Cai, Y. Nanomedicine strategies in con quering and utilizing the cancer hypoxia environment. ACS Nano 2023 , 17 , 20875−20924..

Park, H.; Saravanakumar, G.; Kim, J.; Lim, J.; Kim, W. J. Tumor microenvironment sensitive nanocarriers for bioimaging and therapeutics. Adv. Healthc. Mater. 2021 , 10 , 2000834..

Qu, X.; Zhou, D.; Lu, J.; Qin, D.; Zhou, J.; Liu, H. Cancer nanomedicine in preoperative therapeutics: nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy. Bioact. Mater. 2023 , 24 , 136−152..

Wang, X.; Niu, X.; Sha, W.; Feng, X.; Yu, L.; Zhang, Z.; Wang, W.; Yuan, Z. An oxidation responsive nano-radiosensitizer increases radiotherapy efficacy by remolding tumor vasculature. Biomater. Sci. 2021 , 9 , 6308−6324..

Wang, X.; Niu, X.; Zhang, X.; Zhang, Z.; Gao, X.; Wang, W.; Yuan, Z. Construction of an AuHQ nano-sensitizer for enhanced radiotherapy efficacy through remolding tumor vasculature. J. Mater. Chem. B 2021 , 9 , 4365−4379..

Qian, L.; Li, Q.; Ding, Z.; Luo, K.; Su, J. ; Chen, J.; Zhu, G.; Gan, Z.; Yu, Q. Prodrug nanosensitizer overcomes the radiation resistance of hypoxic tumor. ACS Appl. Mater. Interfaces 2022 , 14 , 56454−56470..

Xie, Y.; Lu, X.; Wang, Z.; Liu, M.; Liu, L.; Wang, R.; Yang, K.; Xiao, H.; Li, J.; Tang, X.; Liu, H. A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma. Biomater. Sci. 2022 , 10 , 6791−6803..

Tang, X.; Du, X.; Yu, Y.; Qin, M.; Qian, L.; Zhang, M.; Yang, Y.; Yu, Q.; Gan, Z. Deep-penetrating triple-responsive prodrug nanosensitizer actuates efficient chemoradiotherapy in pancreatic ductal adenocarcinoma models. Small 2022 , 18 , 2202834..

Yao, L.; Feng, L.; Tao, D.; Tao, H.; Zhong, X.; Liang, C.; Zhu, Y.; Hu, B.; Liu, Z.; Zheng, Y. Perfluorocarbon nanodroplets stabilized with cisplatin-prodrug-constructed lipids enable efficient tumor oxygenation and chemo-radiotherapy of cancer. Nanoscale 2020 , 12 , 14764−14774..

Yang, X.; Wang, Y.; Mao, T.; Wang, Y.; Liu, R.; Yu, L.; Ding, J. An oxygen-enriched thermosensitive hydrogel for the relief of a hypoxic tumor microenvironment and enhancement of radiotherapy. Biomater. Sci. 2021 , 9 , 7471−7482..

Xu, T.; Zheng, D.; Chen, M.; Song, L.; Liu, Z.; Cheng, Y.; Zhao, Y.; Huang, L.; Li, Y.; Yang, Z.; Li, C.; Dong, B.; Jing, J.; Shi, H. A cisplatin prodrug-based self-assembling ozone delivery nanosystem sensitizes radiotherapy in triple-negative breast cancer. Acta Pharm. Sin. B 2025 , 15 , 2703−2722..

Lv, S.; Long, W.; Chen, J.; Ren, Q.; Wang, J.; Mu, X.; Liu, H.; Zhang, X.; Zhang, R. Dual pH-triggered catalytic selective Mn clusters for cancer radiosensitization and radioprotection. Nanoscale 2020 , 12 , 548−557..

Zhang, R.; Chen, L.; Liang, Q.; Xi, J.; Zhao, H.; Jin, Y.; Gao, X.; Yan, X.; Gao, L.; Fan, K. Unveiling the active sites on ferrihydrite with apparent catalase-like activity for potentiating radiotherapy. Nano Today 2021 , 41 , 101317..

Yang, C.; Mi, X.; Su, H.; Yang, J.; Gu, Y.; Zhang, L.; Sun, W.; Liang, X.; Zhang, C. GE11-PDA-Pt@USPIOs nano-formulation for relief of tumor hypoxia and MRI/PAI-guided tumor radio-chemotherapy. Biomater. Sci. 2019 , 7 , 2076−2090..

Zhang, R.; Guo, L.; Li, Q.; Lia ng, Y.; Liao, Y.; Xu, H.; Liu, C.; Zhou, G.; Wang, L.; Xu, S.; Yuan, M. Biodegradable carrier-free nanomedicine via self-assembly of pure drug molecules for triple sensitization of radiotherapy. ACS Nano 2025 , 19 , 16355−16371..

Wang, H.; Jia, D.; Yuan, D.; Yin, X.; Yuan, F.; Wang, F.; Shi, W.; Li, H.; Zhu, L.; Fan, Q. Dimeric Her2-specific affibody mediated cisplatin-loaded nanoparticles for tumor enhanced chemo-radiotherapy. J. Nanobiotechnol. 2021 , 19 , 138..

Zhang, L.; Du, X.; Li, Q.; Qian, L.; Chen, J.; Liu, C.; Yu, Q.; Gan, Z. A multimodal therapeutic nanoplatform overcoming tumor hypoxia heterogeneity for improved tumor chemoradiotherapy. Adv. Funct. Mater. 2022 , 32 , 2204629..

Yu, S.; Jiang, Y.; Li, Q.; Li, M.; Su, J.; Lai, S.; Gan, Z.; Ding, Z.; Yu, Q. Nano-sensitizer with self-amplified drug release and hypoxia normalization properties potentiates efficient chemoradiotherapy of pancreatic cancer. Biomaterials 2024 , 310 , 122634..

[Sun, Y.; Miao, H.; Ma, S.; Zhang, L.; You, C.; Tang, F.; Yang, C.; Tian, X.; Wang, F.; Luo, Y.; Lin, X.; Wang, H.; Li, C.; Li, Z.; Yu, H.; Liu, X.; Xiao, Y.; Gong, Y.; Zhang, J.; Quan, H.; Xie, C. FePt-Cys nanoparticles induce ROS-dependent cell toxicity, and enhance chemo-radiation sensitivity of NSCLC cells in vivo and in vitro. Cancer Lett . 2018, 418 , 27−40..

Ma, Y.; Tang, X.; Xu, Y.; Jiang, W.; Xin, Y.; Zhao, W.; He, X.; Lu, L.; Zhan, M. Nano-enabled coordination platform of bismuth nitrate and cisplatin prodrug potentiates cancer chemoradiotherapy via DNA damage enhancement. Biomater. Sci. 2021 , 9 , 3401−3409..

Zhang, J.; Liu, Y.; Wang, X.; Du, J.; Song, K.; Li, B.; Chang, H.; Ouyang, R.; Miao, Y.; Sun, Y.; Li, Y. Nanozyme-incorporated biodegradable bismuth besoporous radiosensitizer for tumor microenvironment-modulated hypoxic tumor thermoradiotherapy. ACS Appl. Mater. Interfaces 2020 , 12 , 57768−57781..

Cheng, W.; He, S.; Chen, Q.; Song, X.; Lu, C.; Yang, H. X-ray induced persistent type I photodynamic therapy with enhanced hypoxia tolerance and chemoradiotherapy. Nano Lett. 2025 , 25 , 4549−4559..

Chen, J.; Cui, J.; Jiao, B.; Zheng, Z.; Yu, H.; Wang, H.; Zhang, G.; Lai, S.; Gan, Z.; Yu, Q. Biomimetic nanosensitizer potentiates efficient glioblastoma gene-radiotherapy through synergistichypoxia mitigation and PLK1 silencing. ACS Appl. Mater. Interfaces 2024 , 16 , 58241−58261..

Xiao, X.; Wang, Y.; Chen, J.; Qin, P.; Chen, P.; Zhou, D.; Pan, Y. Self-targeting platinum(IV) amphiphilic prodrug nano-assembly as radiosensitizer for synergistic and safe chemoradiotherapy of hepatocellular carcinoma. Biomaterials 2022 , 289 , 121793..

Jin, Y.; Li, D.; Zheng, X.; Gao, M.; Wang, W.; Zhang, X.; Kang, W.; Zhang, C.; Wu, S.; Dai, R.; Zheng, Z.; Zhang, R. A novel activatable nanoradiosensitizer for second near-infrared fluorescence imaging-guided safe-dose synergetic chemo-radiotherapy of rheumatoid arthritis. Adv. Sci. 2024 , 11 , 2308905..

Pi, F.; Deng, X.; Xue, Q.; Zheng, L.; Liu, H.; Yang, F.; Chen, T. Alleviating the hypoxic tumor microenvironment with MnO 2 -coated CeO 2 nanoplatform for magnetic resonance imaging guided radiotherapy. J. Nanobiotechnol. 2023 , 21 , 90..

Guo, Y.; Fang, M.; Zhang, S.; Zhou, Z.; Tian, Z.; You, H.; Chen, Y.; Zhou, J.; Yang, X.;Bi, Y.; Jiang, C.; Sun, T. PROTAC-loaded nanocapsules degrading BRD4 for radio-chemotherapy sensitization in glioblastoma. Acta Pharm. Sin. B 2025 , 15 , 5050−5070..

Chen, J.; Shen, Y.; Yu, Q.; Gan, Z. Paclitaxel prodrug nanomedicine for potential CT-imaging guided breast cancer therapy. Chinese J. Polym. Sci. 2023 , 41 , 1747−1759..

[Hu, F.; Ding, Y.; Deng, C.; Zhang, J.; Qu, W.; Rong, Y.; Chen, N.; Zhou, M.; An, F. SO 2 gas potentiator engineered for self-amplifying chemo-radiotherapy in breast tumors. Chin. Chem. Lett . 2025, 112277..

Hou, M.; Zhu, K.; Hu, H.; Zheng, S.; Wu, Z.; Ren, Y.; Wu, B.; Qi, L.; Wu, D.; Xu, Y.; Yan, C.; Zhao, B. Rapid synthesis of ‘yolk-shell’-like nanosystem for MR molecular and chemo-radio sensitization. J. Control. Release 2022 , 347 , 55−67..

Luan, S.; Xie, R.; Yang, Y.; Xiao, X.; Zhou, J.; Li, X.; Fang, P.; Zeng, X.; Yu, X.; Chen, M.; Gao, H.; Yuan, Y. Acid-responsive aggregated gold nanoparticles for radiosensitization and synergistic chemoradiotherapy in the treatment of esophageal cancer. Small 2022 , 18 , 2200115..

Xiao, W.; Yang, X.; Wang, M.; Jiang, Z.; Zhang, H.; Gong, M.; Zhao, L.; Song, J.; Fu, Q. Enzyme-sequential respo nsive core-satellite nanomedicine enables activatable near-infrared-II photoacoustic imaging-guided chemotherapy cascade-enhanced radiotherapy. J. Nanobiotechnol. 2025 , 23 , 440..

Du, L.; Zhu, G.; Xu, Y.; Han, B.; Wang, Y.; Zhu, M.; Meng, Y.; Chen, H.; Yu, Z. Integrated radiochemotherapy study of ZIF-8 coated with osteosarcoma-platelet hybrid membranes for the delivery of Dbait and Adriamycin. Front. Bioeng. Biotechnol. 2023 , 11 , 1147064..

[He, C.; Zhang, Z.; Ding, Y.; Xue, K.; Wang, X.; Yang, R.; An, Y.; Liu, D.; Hu, C.; Tang, Q. LRP1-mediated pH-sensitive polymersomes facilitate combination therapy of glioblastoma in vitro and in vivo. J. Nanobiotechnol . 2021, 19 , 1−17..

Li, X.; Yu, L.; Zhang, C.; Niu, X.; Sun, M.; Yan, Z.; Wang, W.; Yuan, Z. Tumor acid microenvironment-activated self-targeting & splitting gold nanoassembly for tumor chemo-radiotherapy. Bioact. Mater. 2022 , 7 , 377−388..

Wang, Y.; Han, X.; Zhang, S.; Wang, L.; Sun, S.; Xue, C.; Yao, T. Dual-targeted Pt@Ce-MOF nanoplatform enhances radiotherapy efficacy via tumor-specific delivery and mitochondrial dysfunction in breast cancer. Biopolymers 2025 , 116 , e70054..

Mirzaghavami, P. S.; Khoei, S.; Khoee, S.; Shirvalilou, S.; Mahdavi, S. R.; Pirhajati Mahabadi, V. Radio-sensitivity enhancement in HT29 cells through magnetic hyperthermia in combination with targeted nano-carrier of 5-flourouracil. Mater. Sci. Eng. C Mater. Biol. Appl. 2021 , 124 , 112043..

Shi, Y.; Ding, S.; Wang, Z.; Li, L.; Wang, J.; Mehdizadeh, S.; Pilehvar, Y. Hydrogel-mediated tri-modal nanoplatform for localized colorectal cancer therapy via smart chemo–photothermal–radiotherapy. J. Biol. Eng. 2026 , 20 , 42..

Su, L.; Zhu, K.; Ge, X.; Wu, Y.; Zhang, J.; Wang, G.; Liu, D.; Chen, L.; Li, Q.; Chen, J.; Song, J. X-ray activated nanoprodrug for visualization of cortical microvascular alterations and NIR-II image-guided chemo-radiotherapy of glioblastoma. Nano Lett. 2024 , 24 , 3727−3736..

Sun, L.; Shen, F.; Tian, L.; Tao, H.; Xiong, Z.; Xu, J.; Liu, Z. ATP-responsive smart hydrogel releasing immune adjuvant synchronized with repeated chemotherapy or radiotherapy to boost antitumor immunity. Adv. Mater. 2021 , 33 , 2007910..

Liu, C.; Lin, R.; Lai, H.; Pi, F.; Xue, Q.; Chen, T.; He, W. Thermosensitive selenium hydrogel boosts antitumor immune response for hepatocellular carcinoma chemoradiotherapy. Nano Today 2023 , 50 , 101823..

Zhu, Y.; Zhang, S.; Lai, Y.; Pan, J.; Chen, F.; Wang, T.; Wang, F.; Xu, Z.; Yang, W.; Yu, H. Self-cooperative prodrug nanovesicles migrate immune evasion to potentiate chemoradiotherapy in head and neck cancer. Adv. Sci. 2022 , 9 , 2203263..

Chen, Y.; Liu, S.; Gao, P.; Pan, W.; Shi, M.; Wang, J.; Li, N.; Tang, B. Reprogramming tumor-immune cell communication with a radiosensitive nanoregulator for immunotherapy. Sci. China Mater. 2023 , 66 , 352−362..

Deng, Z.; Xi, M.; Zhang, C.; Wu, X.; Li, Q.; Wang, C.; Fang, H.; Sun, G.; Zhang, Y.; Yang, G.; Liu, Z. Biomineralized MnO 2 nanoplatforms mediated delivery of immune checkpoint inhibitors with STING pathway activation to potentiate cancer radio-immunotherapy. ACS Nano 2023 , 17 , 4495−4506..

Graham, K.; Unger, E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int. J. Nanomed. 2018 , 13 , 6049−6058..

Zeng, W.; Liu, P.; Pan, W.; Singh, S. R.; Wei, Y. Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett. 2015 , 356 , 263−267..

[Ma, J.; Li, N.; Wang, J.; Liu, Z.; Han, Y.; Zeng, Y. In vivo synergistic tumor therapies based on copper sulfide photothermal therapeutic nanoplatforms. Exploration 2023, 3 , 20220161..

Chen, G.; Wu, K.; Li, H.; Xia, D.; He, T. Role of hypoxia in the tumor microenvironment and targeted therapy. Front. Oncol. 2022 , 12 , 961637..

Rockwell, S.; Dobrucki, I. T.; Kim, E. Y.; Marrison, S. T.; Vu, V. T. Hypoxia and radiation therapy: past history, ongoing research, and future promise. Curr. Mol. Med. 2009 , 9 , 442−458..

Gray, L. H.; Conger, A. D.; Ebert, M.; Hornsey, S.; Scott, O. C. A. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 1953 , 26 , 638−648..

Barker, H. E.; Paget, J. T. E.; Khan, A. A.; Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 2015 , 15 , 409−425..

Heckmann, M.; Douwes, K.; Peter, R.; Degitz, K. Vascular activation of adhesion molecule mRNA and cell surface expression by ionizing radiation. Exp. Cell Res. 1998 , 238 , 148−154..

Liu, Z.; Zhao, Q.; Zheng, Z.; Liu, S.; Meng, L.; Dong, L.; Jiang, X. Vascular normalization in immunotherapy: a promising mechanisms combined with radiotherapy. Biomed. Pharmacother. 2021 , 139 , 111607..

Baker, D. G.; Krochak, R. J. The response of the microvascular system to radiation: a review. Cancer Invest. 1989 , 7 , 287−294..

Ivey, J. W.; Bonakdar, M.; Kanitkar, A.; Davalos, R. V.; Verbridge, S. S. Improving cancer therapies by targeting the physical and chemical hallmarks of the tumor microenvironment. Cancer Lett. 2016 , 380 , 330−339..

Tamura, R.; Tanaka, T.; Akasaki, Y.; Murayama, Y.; Yoshida, K.; Sasaki, H. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med. Oncol. 2019 , 37 , 2..

Wang, Q.; Liang, Q.; Dou, J.; Zhou, H.; Zeng, C.; Pan, H.; Shen, Y.; Li, Q.; Liu, Y.; Leong, D. T.; Jiang, W.; Wang, Y. Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours. Nat. Nanotechnol. 2024 , 19 , 95−105..

Xie, J.; Gong, L.; Zhu, S.; Yong, Y.; Gu, Z.; Zhao, Y. Emerging strategies of nanomaterial-mediated tumor radiosensitization. Adv. Mater. 2019 , 31 , 1802244..

Jiang, H.; Wang, H.; De Ridder, M. Targeting antioxidant enzymes as a radiosensitizing strategy. Cancer Lett. 2018 , 438 , 154−164..

Tafani, M.; Sansone, L.; Limana, F.; Arcangeli, T.; De Santis, E.; Polese, M.; Fini, M.; Russo, M. A. The interplay of reactive oxygen species, hypoxia, inflammation, and sirtuins in cancer initiation and progression. Oxid. Med. Cell. Longev. 2016 , 2016 , 3907147..

Zou, Z.; Chang, H.; Li, H.; Wang, S. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis 2017 , 22 , 1321−1335..

Jia, S.; Ge, S.; Fan, X.; Leong, K. W.; Ruan, J. Promoting reactive oxygen species generation: a key strategy in nanosensitizer-mediated radiotherapy. Nanomedicine 2021 , 16 , 759−778..

Kennel, K. B.; Greten, F. R. Immune cell - produced ROS and their impact on tumor growth and metastasis. Redox Biol. 2021 , 42 , 101891..

Dabbour, N. M.; Salama, A. M.; Donia, T.; Al-Deeb, R. T.; Abd Elghane, A. M.; Badry, K. H.; Loutfy, S. A. Managing GSH elevation and hypoxia to overcome resistance of cancer therapies using functionalized nanocarriers. J. Drug Deliv. Sci. Technol. 2022 , 67 , 103022..

Sonveaux, P. ROS and radiotherapy: more we care. Oncotarget 2017 , 8 , 35482−35483..

Webb, B. A.; Chimenti, M.; Jacobson, M. P.; Barber, D. L. Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer 2011 , 11 , 671−677..

Persi, E.; Duran-Frigola, M.; Damaghi, M.; Roush, W. R.; Aloy, P.; Cleveland, J. L.; Gillies, R. J.; Ruppin, E. Systems analysis of intracellular pH vulnerabilities for cancer therapy. Nat. Commun. 2018 , 9 , 2997..

[Zheng, T.; Jäättelä, M.; Liu, B. pH gradient reversal fuels cancer progression. Int. J. Biochem. Cell 2020, 125 , 105796..

Bogdanov, A.; Bogdanov, A.; Chubenko, V.; Volkov, N.; Moiseenko, F.; Moiseyenko, V. Tumor acidity: from hallmark of cancer to target of treatment. Front. Oncol. 2022 , 12 , 979154..

[Mahoney, B. P.; Raghunand, N.; Baggett, B.; Gillies, R. J. Tumor acidity, ion trapping and chemotherapeutics: I. acid pH affects the distribution of chemotherapeutic agents in vitro. Biochem. Pharmacol . 2003, 66 , 1207−1218..

Sauvant, C.; Nowak, M.; Wirth, C.; Schneider, B.; Riemann, A.; Gekle, M.; Thews, O. Acidosis induces multi-drug resistance in rat prostate cancer cells (AT1) in vitro and in vivo by increasing the activity of the p-glycoprotein via activation of p38. Int. J. Cancer 2008 , 123 , 2532−2542..

Thews, O.; Gassner, B.; Kelleher, D. K.; Schwerd, G.; Gekle, M. Impact of extracellular acidity on the activity of P-glycoprotein and the cytotoxicity of chemotherapeutic drugs. Neoplasia 2006 , 8 , 143−152..

Hu, P.; Li, T.; Lin, J.; Qiu, M.; Wang, D.; Liu, Z.; Chen, Z.; Yang, L.; Zhang, X.; Zhao, Q.; Chen, Y.; Lu, Y.; Wu, Q.; Pu, H.; Zeng, Z.; Xie, D.; Ju, H.; Luo, H.; Xu, R. VDR–SOX2 signaling promotes colorectal cancer stemness and malignancy in an acidic microenvironment. Signal Transduction Targeted Ther. 2020 , 5 , 183..

Bristow, R. G.; Hill, R. P. Hypoxia, DNA repair and genetic instability. Nat. Rev. Cancer 2008 , 8 , 180−192..

Huntington, K. E.; Louie, A.; Zhou, L.; Seyhan, A. A.; Maxwell, A. W.; El-Deiry, W. S. Colorectal cancer extracellular acidosis decreases immune cell killing a nd is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles. Am. J. Cancer Res. 2022 , 12 , 138−151..

Fischer, K.; Hoffmann, P.; Voelkl, S.; Meidenbauer, N.; Ammer, J.; Edinger, M.; Gottfried, E.; Schwarz, S.; Rothe, G.; Hoves, S.; Renner, K.; Timischl, B.; Mackensen, A.; Kunz-Schughart, L.; Andreesen, R.; Krause, S. W.; Kreutz, M. Inhibitory effect of tumor cell–derived lactic acid on human T cells. Blood 2007 , 109 , 3812−3819..

[Klaus, T.; Deshmukh, S. pH-responsive antibodies for therapeutic applications. J. Biomed. Sci . 2021, 28 , 11..

[Li, Z.; Huang, J.; Wu, J. pH-sensitive nanogels for drug delivery in cancer therapy. Biomater. Sci . 2021, 9 , 574−589..

Morarasu, S.; Morarasu, B. C.; Ghiarasim, R.; Coroaba, A.; Tiron, C.; Iliescu, R.; Dimofte, G. M. Targeted cancer therapy via pH-functionalized nanoparticles: a scoping review of methods and outcomes. Gels 2022 , 8 , 232..

Li, X.; Yue, R.; Guan, G.; Zhang, C.; Zhou, Y.; Song, G. Recent development of pH-responsive theranostic nanoplatforms for magnetic resonance imaging-guided cancer therapy. Exploration 2023 , 3 , 20220002..

[Le, A., in The heterogeneity of cancer metabolism , Springer Nature, 2021 , pp. 3−15..

[Oshima, N.; Ishida, R.; Kishimoto, S.; Beebe, K.; Brender, J. R.; Yamamoto, K.; Urban, D.; Rai, G.; Johnson, M. S.; Benavides, G. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep . 2020, 30 , 1798−1810..

Koltai, T. Triple-edged therapy targeting intracellular alkalosis and extracellular acidosis in cancer. Semin. Cancer Biol. 2017 , 43 , 139−146..

Pillai, S. R.; Damaghi, M.; Marunaka, Y.; Spugnini, E. P.; Fais, S.; Gillies, R. J. Causes, consequences, and therapy of tumors acidosis. Cancer Metastasis Rev. 2019 , 38 , 205−222..

Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 2011 , 144 , 646−674..

Heldin, C. H.; Rubin, K.; Pietras, K.; Östman, A. High interstitial fluid pressure — an obstacle in cancer therapy. Nat. Rev. Cancer 2004 , 4 , 806−813..

DuFort, C. C.; DelGiorno, K. E.; Carlson, M. A.; Osgood, R. J.; Zhao, C.; Huang, Z.; Thompson, C. B.; Connor, R. J.; Thanos, C. D.; Scott Brockenbrough, J.; Provenzano, P. P.; Frost, G. I.; Michael Shepard, H.; Hingorani, S. R. Interstitial pressure in pancreatic ductal adenocarcinoma is dominated by a gel-fluid phase. Biophys. J. 2016 , 110 , 2106−2119..

Cirri, P.; Chiarugi, P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012 , 31 , 195−208..

Liu, H.; Zhao, H.; Sun, Y. Tumor microenvironment and cellular senescence: understanding therapeutic resistance and harnessing strategies. Semin. Cancer Biol. 2022 , 86 , 769−781..

Goenka, A.; Khan, F.; Verma, B.; Sinha, P.; Dmello, C. C.; Jogalekar, M. P.; Gangadaran, P.; Ahn, B. C. Tumor microenvironment signaling and therapeutics in cancer progression. Cancer Commun. 2023 , 43 , 525−561..

Emons, G.; Spitzner, M.; Reineke, S.; Möller, J.; Auslander, N.; Kramer, F.; Hu, Y.; Beissbarth, T.; Wolff, H. A.; Rave-Fränk, M.; Heßmann, E.; Gaedcke, J.; Ghadimi, B. M.; Johnsen, S. A.; Ried, T.; Grade, M. Chemoradiotherapy resistance in colorectal cancer cells is mediated by Wnt/ β -catenin signaling. Mol. Cancer Res. 2017 , 15 , 1481−1490..

Sun, Y.; Campisi, J.; Higano, C.; Beer, T. M.; Porter, P.; Coleman, I.; True, L.; Nelson, P. S. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 2012 , 18 , 1359−1368..

Chen, F.; Long, Q.; Fu, D.; Zhu, D.; Ji,Y.; Han, L.; Zhang, B.; Xu, Q.; Liu, B.; Li, Y.; Wu, S.; Yang, C.; Qian, M.; Xu, J.; Liu, S.; Cao, L.; Chin, Y. E.; Lam, E. W. F.; Coppé, J. P.; Sun, Y. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat. Commun. 2018 , 9 , 4315..

Laberge, R. M.; S un, Y.; Orjalo, A. V.; Patil, C. K.; Freund, A.; Zhou, L.; Curran, Samuel C.; Davalos, A. R.; Wilson-Edell, K. A.; Liu, S.; Limbad, C.; Demaria, M.; Li, P.; Hubbard, G. B.; Ikeno, Y.; Javors, M.; Desprez, P. Y.; Benz, C. C.; Kapahi, P.; Nelson, P. S.; Campisi, J. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 2015 , 17 , 1049−1061..

Zhang, B.; Fu, D.; Xu, Q.; Cong, X.; Wu, C.; Zhong, X.; Ma, Y.; Lv, Z.; Chen, F.; Han, L.; Qian, M.; Chin, Y. E.; Lam, E. W. F.; Chiao, P.; Sun, Y. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat. Commun. 2018 , 9 , 1723..

Rajbhandary, S.; Dhakal, H.; Shrestha, S. Tumor immune microenvironment (TIME) to enhance antitumor immunity. Eur. J. Med. Res. 2023 , 28 , 169..

Khalaf, K.; Hana, D.; Chou, J. T.; Singh, C.; Mackiewicz, A.; Kaczmarek, M. Aspects of the tumor microenvironment involved in immune resistance and drug resistance. Front. Immunol. 2021 , 12 , 656364..

Sridharan, V.; Margalit, D. N.; Lynch, S. A.; Severgnini, M.; Zhou, J.; Chau, N. G.; Rabinowits, G.; Lorch, J. H.; Hammerman, P. S.; Hodi, F. S.; Haddad, R. I.; Tishler, R. B.; Schoenfeld, J. D. Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer. Br. J. Cancer 2016 , 115 , 252−260..

Burnette, B. C.; Liang, H.; Lee, Y.; Chlewicki, L.; Khodarev, N. N.; Weichselbaum, R. R.; Fu, Y. X.; Auh, S. L. The efficacy of radiotherapy relies upon induction of type I interferon–dependent innate and adaptive immunity. Cancer Res. 2011 , 71 , 2488−2496..

Schuler, P. J.; Harasymczuk, M.; Schilling, B.; Saze, Z.; Strauss, L.; Lang, S.; Johnson, J. T.; Whiteside, T. L. Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer. Clin. Cancer. Res. 2013 , 19 , 6585−6596..

Al-Taei, S.; Banner, R.; Powell, N.; Evans, M.; Palaniappan, N.; Tabi, Z.; Man, S. Decreased HPV-specific T cell responses and accumulation of immunosuppressive influences in oropharyngeal cancer patients following radical therapy. Cancer Immunol. Immunother. 2013 , 62 , 1821−1830..

Van Meir, H.; Nout, R. A.; Welters, M. J. P.; Loof, N. M.; De Kam, M. L.; Van Ham, J. J.; Samuels, S.; Kenter, G. G.; Cohen, A. F.; Melief, C. J. M. Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. Oncoimmunology 2017 , 6 , e1267095..

Bai, R.; Cui, J. Development of immunotherapy strategies targeting tumor microenvironment is fiercely ongoing. Front. Immunol. 2022 , 13 , 890166..

Li, Z.; Di, C.; Li, S.; Yang, X.; Nie, G. Smart nanotherapeutic targeting of tumor vasculature. Acc. Chem. Res. 2019 , 52 , 2703−2712..

Horsman, M. R.; Siemann, D. W. Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res. 2006 , 66 , 11520−11539..

Iversen, A. B.; Busk, M.; Horsman, M. R. Induction of hypoxia by vascular disrupting agents and the significance for their combination with radiation therapy. Acta Oncol. 2013 , 52 , 1320−1326..

Li, L.; Wartchow, C. A.; Danthi, S. N.; Shen, Z.; Dechene, N.; Pease, J.; Choi, H. S.; Doede, T.; Chu, P.; Ning, S.; Lee, D. Y.; Bednarski, M. D.; Knox, S. J. A novel antiangiogenesis thera py using an integrin antagonist or anti–Flk-1 antibody coated 90 Y-labeled nanoparticles. Int. J. Radiat. Oncol. Biol., Phys. 2004 , 58 , 1215−1227..

Zheng, R.; Li, F.; Li, F.; Gong, A. Targeting tumor vascularization: promising strategies for vascular normalization. J. Cancer Res. Clin. Oncol. 2021 , 147 , 2489−2505..

El Alaoui-Lasmaili, K.; Faivre, B. Antiangiogenic therapy: markers of response, “normalization” and resistance. Crit. Rev. Oncol. Hematol. 2018 , 128 , 118−129..

McGee, M. C.; Hamner, J. B.; Williams, R. F.; Rosati, S. F.; Sims, T. L.; Ng, C. Y.; Gaber, M. W.; Calabrese, C.; Wu, J.; Nathwani, A. C.; Duntsch, C.; Merchant, T. E.; Davidoff, A. M. Improved intratumoral oxygenation through vascular normalization increases glioma sensitivity to ionizing radiation. Int. J. Radiat. Oncol. Biol., Phys. 2010 , 76 , 1537−1545..

Magnussen, A. L.; Mills, I. G. Vascular normalisation as the stepping stone into tumour microenvironment transformation. Br. J. Cancer 2021 , 125 , 324−336..

Yin, W.; Qiang, M.; Ke, W.; Han, Y.; Mukerabigwi, J. F.; Ge, Z. Hypoxia-responsive block copolymer radiosensitizers as anticancer drug nanocarriers for enhanced chemoradiotherapy of bulky solid tumors. Biomaterials 2018 , 181 , 360−371..

Prasad, P.; Gordijo, C. R.; Abbasi, A. Z.; Maeda, A.; Ip, A.; Rauth, A. M.; DaCosta, R. S.; Wu, X. Y. Multifunctional albumin–MnO 2 nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano 2014 , 8 , 3202−3212..

Feng, L.; Dong, Z.; Liang, C.; Chen, M.; Tao, D.; Cheng, L.; Yang, K.; Liu, Z. Iridium nanocrystals encapsulated liposomes as near-infrared light controllable nanozymes for enhanced cancer radiotherapy. Biomaterials 2018 , 181 , 81−91..

Tremi, I.; Spyratou, E.; Souli, M.; Efstathopoulos, E. P.; Makropoulou, M.; Georgakilas, A. G.; Sihver, L. Requirements for designing an effective metallic nanoparticle (NP)-boosted radiationtherapy (RT). Cancer 2021 , 13 , 3185..

Setua, S.; Ouberai, M.; Piccirillo, S. G.; Watts, C.; Welland, M. Cisplatin-tethered gold nanospheres for multimodal chemo -radiotherapy of glioblastoma. Nanoscale 2014 , 6 , 10865−10873..

Pivovarov, N. A.; Kolmanovich, D. D.; Chukavin, N. N.; Savintseva, I. V.; Popova, N. R.; Shemyakov, A. E.; Filippova, A. D.; Teplonogova, M. A.; Yurkovskaya, A. V.; Zhukov, I. V.; Akkizov, A. Y.; Popov, A. L. Novel cerium- and terbium-doped gadolinium fluoride nanoparticles as radiosensitizers with pronounced radiocatalytic activity. Biomedicines 2025 , 13 , 1537..

Zwiehoff, S.; Johny, J.; Behrends, C.; Landmann, A.; Mentzel, F.; Bäumer, C.; Kröninger, K.; Rehbock, C.; Timmermann, B.; Barcikowski, S. Enhancement of proton therapy efficiency by noble metal nanoparticles is driven by the number and chemical activity of surface atoms. Small 2022 , 18 , 2106383..

Yang, G.; Ji, J.; Liu, Z. Multifunctional MnO 2 nanoparticles for tumor microenvironment modulation and cancer therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2021 , 13 , e1720..

Rahman, M.; Kabir, M.; Islam, T.; Wang, Y.; Meng, Q.; Liu, H.; Chen, S.; Wu, S. Curcumin-loaded ZIF-8 nanomaterials: exploring drug loading efficiency and biomedical performance. ACS Omega 2025 , 10 , 3067−3079..

Young, O.; Ngo, N.; Lin, L.; Stanbery, L.; Creeden, J. F.; Hamouda, D.; Nemunaitis, J. Folate receptor as a biomarker and therapeutic target in solid tumors. Curr. Probl. Cancer 2023 , 47 , 100917..

Hansen, M. F.; Greibe, E.; Skovbjerg, S.; Rohde, S.; Kristensen, A. C. M.; Jensen, T. R.; Stentoft, C.; Kjær, K. H.; Kronborg, C. S.; Martensen, P. M. Folic acid mediates activation of the pro-oncogene STAT3 via the folate receptor alpha. Cell. Signal. 2015 , 27 , 1356−1368..

Girigoswami, K.; Girigoswami, A. Breast cancer progression and its theranostic management via folate-directed targeting of glycoprotein receptor. Med. Sci. 2025 , 13 , 275..

Liu, X.; Yuan, Z.; Tang, Z.; Chen, Q.; Huang, J.; He, L.; Chen, T. Selenium-driven enhancement of synergistic cancer chemo-/radiotherapy by targeting nanotherapeutics. Biomater. Sci. 2021 , 9 , 4691−4700..

Farran, B.; Montenegro, R. C.; Kasa, P.; Pavitra, E.; Huh, Y. S.; Han, Y. K.; Kamal, M. A.; Nagaraju, G. P.; Rama Raju, G. S. Folate-conjuga ted nanovehicles: strategies for cancer therapy. Mater. Sci. Eng. C Mater. Biol. Appl. 2020 , 107 , 110341..

Sakunrangsit, N.; Khantasup, K.; Pornputtipong, N.; Suppipat, K.; Hirankarn, N.; Tawinwung, S. Human VH-antibody-based CAR T cells targeting folate receptor-alpha show enhanced persistence and reduced T-cell exhaustion against ovarian cancer. Biomed. Pharmacother. 2026 , 197 , 119169..

Campbell, I. D.; Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 2011 , 3 , a004994..

LaFlamme, S. E.; Auer, K. L. Integrin signaling. Semin. Cancer Biol. 1996 , 7 , 111−118..

Brooks, P. C.; Montgomery, A. M. P.; Rosenfeld, M.; Reisfeld, R. A.; Hu, T.; Klier, G.; Cheresh, D. A. Integrin α v β 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994 , 79 , 1157−1164..

Wang, K.; Li, Z. L.; Huang, L. Y.; Yao, C. J.; Crawford, D. R.; Wang, C. Y.; Mo, J. K.; Shi h, Y. J.; Lin, H. Y.; WhangPeng, J. Integrin α v β 3 as a non-genomic estrogen receptor in breast cancer for signaling pathways and crosstalk. Cells 2025 , 14 , 1832..

Ruoslahti, E. RGD and other recognition sequences for integrins. Annu. Rev. Cell Dev. Biol. 1996 , 12 , 697−715..

Videtic, G. M. M.; Fisher, B. J.; Perera, F. E.; Bauman, G. S.; Kocha, W. I.; Taylor, M.; Vincent, M. D.; Plewes, E. A.; Engel, C. J.; Stitt, L. W. Preoperative radiation with concurrent 5-fluorouracil continuous infusion for locally advanced unresectable rectal cancer. Int. J. Radiat. Oncol. Biol., Phys. 1998 , 42 , 319−324..

[Valencia-Lazcano, A. A.; Hassan, D.; Pourmadadi, M.; Shamsabadipour, A.; Behzadmehr, R.; Rahdar, A.; Medina, D. I.; Díez-Pascual, A. M. 5-Fluorouracil nano-delivery systems as a cutting-edge for cancer therapy. Eur. J. Med. Chem . 2023, 246 , 114995..

Xue, C.; Zhang, X.; Yu, W.; Lin, H.; Zhang, J.; Liu, J.; Weng, Z.; Ouyang, M.; Lin, X. GLI2-HRD1 axis facilitates 5-FU resistance in gastric cancer cells by regulating ubiquitination degradation of UCK2. Transl. Oncol. 2025 , 58 , 102423..

Lv, B.; Wang, Y.; Ma, D.; Cheng, W.; Liu, J.; Yong, T.; Chen, H.; Wang, C. Immunotherapy: reshape the tumor immune microenvironment. Front. Immunol. 2022 , 13 , 844142..

McFarland, H. I.; Puig, M.; Grajkowska, L. T.; Tsuji, K.; Lee, J. P.; Mason, K. P.; Verthelyi, D.; Rosenberg, A. S. Regulatory T cells in γ irradiation-induced immune suppression. PLoS One 2012 , 7 , e39092..

Mougiakakos, D.; Johansson, C. C.; Jitschin, R.; Böttcher, M.; Kiessling, R. Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood 2011 , 117 , 857−861..

Suzuki, E.; Kapoor, V.; Jassar, A. S.; Kaiser, L. R.; Albelda, S. M. Gemcitabine selectively eliminates splenic Gr-1 + /CD11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer. Res. 2005 , 11 , 6713−6721..

[Vincent, J.; Mignot, G.; Chalmin, F.; L adoire, S.; Bruchard, M.; Chevriaux, A.; Martin, F.; Apetoh, L.; Rébé, C.; Ghiringhelli, F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell–dependent antitumor immunity. Cancer Res . 2010, 70 , 3052-3061..

Apetoh, L.; Ghiringhelli, F.; Tesniere, A.; Criollo, A.; Ortiz, C.; Lidereau, R.; Mariette, C.; Chaput, N.; Mira, J. P.; Delaloge, S.; André, F.; Tursz, T.; Kroemer, G.; Zitvogel, L. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol. Rev. 2007 , 220 , 47−59..

Apetoh, L.; Ghiringhelli, F.; Tesniere, A.; Obeid, M.; Ortiz, C.; Criollo, A.; Mignot, G.; Maiuri, M. C.; Ullrich, E.; Saulnier, P.; Yang, H.; Amigorena, S.; Ryffel, B.; Barrat, F. J.; Saftig, P.; Levi, F.; Lidereau, R.; Nogues, C.; Mira, J. P.; Chompret, A.; Joulin, V.; Clavel-Chapelon, F.; Bourhis, J.; André, F.; Delaloge, S.; Tursz, T.; Kroemer, G.; Zitvogel, L. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 2007 , 13 , 1050−1059..

Apetoh, L.; Tesniere, A.; Ghiringhelli, F.; Kroemer, G.; Zitvogel, L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 2008 , 68 , 4026−4030..

Kono, K.; Mimura, K.; Kiessling, R. Immunogenic tumor cell death induced by chemoradiotherapy: molecular mechanisms and a clinical translation. Cell Death Dis. 2013 , 4 , e688..

Moridikia, A.; Montazersaheb, S.; Molavi, O. Manipulation of tumor microenvironment by induction of immunogenic cell death and immune check point inhibitors for enhancing the efficacy of cancer treatments. Biomed. Pharmacother. 2026 , 196 , 119118..

Pointer, K. B.; Pitroda, S. P.; Weichselbaum, R. R. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 2022 , 8 , 9−20..

Feng, C. H.; Mell, L. K.; Sharabi, A. B.; McHale, M.; Mayadev, J. S. Immunotherapy with radiotherapy and chemoradiotherapy for cervical cancer. Semin. Radiat. Oncol. 2020 , 30 , 273−280..

Dong, Q.; Xue, T.; Yan, H.; Liu, F.; Liu, R.; Zhang, K.; Chong, Y.; Du, J.; Zhang, H. Radiotherapy combined with nano-biomaterials for cancer radio-immunotherapy. J. Nanobiotechnol. 2023 , 21 , 395..

Zhou, J.; Zhang, Y.; Dong, F.; Matsuyama, K.; Tanaka, Y.; Wu, L. Mechanisms of tumor radiosensitization: a perspective of nano-radiotherapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2025 , 17 , e70035..

Rosenthal, D. I.; Yom, S. S.; Liu, L.; Machtay, M.; Algazy, K.; Weber, R. S.; Weinstein, G. S.; Chalian, A. A.; Miller, L. K.; Rockwell, K.; Tonda, M.; Schnipper, E.; Hershock, D. A phase I study of SPI-077 (stealth® liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer. Invest. New Drugs 2002 , 20 , 343−349..

Koukourakis, M. I.; Giatromanolaki, A.; Pitiakoudis, M.; Kouklakis, G.; Tsoutsou, P.; Abatzoglou, I.; Panteliadou, M.; Sismanidou, K.; Sivridis, E.; Boulikas, T. Concurrent liposomal cisplatin (lipoplatin), 5-fluorouracil and radiotherapy for the treatment of locally advanced gastric cancer: a phase I/II study. Int. J. Radiat. Oncol. Biol., Phys. 2010 , 78 , 150−155..

Zeng, J.; Cui, X.; Cheng, L.; Chen, Y.; Du, X.; Sheng, L. Liposome-paclitaxel and carboplatin combination chemoradiotherapy for patients with locally advanced esophageal squamous cell carcinoma. Cancer Radiother. 2021 , 25 , 441−446..

Chen, G.; Sheng, L.; Du, X. Efficacy and safety of liposome-paclitaxel and carboplatin based concurrent chemoradiotherapy for locally advanced lung squamous cell carcinoma. Cancer Chemother. Pharmacol. 2018 , 82 , 505−510..

Beier, C. P.; Schmid, C.; Gorlia, T.; Kleinletzenberger, C.; Beier, D.; Grauer, O.; Steinbrecher, A.; Hirschmann, B.; Brawanski, A.; Dietmaier, C.; Jauch-Worley, T.; Kölbl, O.; Pietsch, T.; Proescholdt, M.; Rümmele, P.; Muigg, A.; Stockhammer, G.; Hegi, M.; Bogdahn, U.; Hau, P. RNOP-09: PEGylated liposomal doxorubicin and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma: a phase II study. BMC Cancer 2009 , 9 , 308..

Ananda, S.; Nowak, A. K.; Cher, L.; Dowling, A.; Brown, C.; Simes, J.; Rosenthal, M. A. Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. J. Clin. Neurosci. 2011 , 18 , 1444−1448..

Tsujimoto, A.; Sudo, K.; Nakamura, K.; Kita, E.; Hara, R.; Takayama, W.; Ishii, H.; Yamaguchi, T. Gemcitabine plus nab-paclitaxel for locally advanced or borderline resectable pancreatic cancer. Sci. Rep. 2019 , 9 , 16187..

Philip, P. A.; Lacy, J.; Portales, F.; Sobrero, A.; Pazo-Cid, R.; Manzano Mozo, J. L.; Kim, E. J.; Dowden, S.; Zakari, A.; Borg, C.; Terrebonne, E.; Rivera, F.; Sastre, J.; Bathini, V.; López-Trabada, D.; Asselah, J.; Saif, M. W.; Shiansong Li, J.; Ong, T. J.; Nydam, T.; Hammel, P. Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study. Lancet. Gastroenterol. 2020 , 5 , 285−294..

Jiang, H.; Li, Q.; Chen, B.; Xi, M.; Makelike, K.; Liu, S.; Hu, Y.; Zhu, Y. Phase I study of cisplatin and nanoparticle albumin-bound-paclitaxel combined with concurrent radiotherapy in locally advanced esophageal squamous cell carcinoma. Cancer Med. 2023 , 12 , 15187−15198..

Oppelt, P.; Ley, J.; Daly, M.; Rich, J.; Paniello, R.; Jackson, R. S.; Pipkorn, P.; Liu, J.; Gay, H.; Palka, K.; Neupane, P.; Powell, S.; Spanos, W. C.; Gitau, M.; Zevallos, J.; Thorstad, W.; Adkins, D. Nab-paclitaxel and cisplatin followed by cisplatin and radiation (Arm 1) and nab-paclitaxel followed by cetuximab and radiation (Arm 2) for locally advanced head and neck squamous cell carcinoma: a multicenter, nonrandomized phase 2 trial. Med. Oncol. 2021 , 38 , 35..

Weiss, J.; Gilbert, J.; Deal, A. M.; Weissler , M.; Hilliard, C.; Chera, B.; Murphy, B.; Hackman, T.; Liao, J. J.; Grilley Olson, J.; Hayes, D. N. Induction chemotherapy with carboplatin, nab-paclitaxel and cetuximab for at least N2b nodal status or surgically unresectable squamous cell carcinoma of the head and neck. Oral Oncol. 2018 , 84 , 46−51..

Adkins, D.; Ley, J.; Michel, L.; Wildes, T. M.; Thorstad, W.; Gay, H. A.; Daly, M.; Rich, J.; Paniello, R.; Uppaluri, R.; Jackson, R.; Trinkaus, K.; Nussenbaum, B. Nab-paclitaxel, cisplatin, and 5-fluorouracil followed by concurrent cisplatin and radiation for head and neck squamous cell carcinoma. Oral Oncol. 2016 , 61 , 1−7..

Tanaka, H.; Hasegawa, Y.; Makiguchi, T.; Okumura, F.; Tabe, C.; Shiratori, T.; Ishioka, Y.; Itoga, M.; Taima, K.; Yokouchi, J.; Hatayama, Y.; Aoki, M.; Tasaka, S. A phase I/II study of biweekly carboplatin and nab-paclitaxel with concurrent radiotherapy for patients with locally advanced unresectable stage III non–small-cell lung cancer. Clin. Lung Cancer 2021 , 22 , 42−48..

Omori, S.; Harada, H.; Mori, K.; Hisamatsu, Y.; Tsuboguchi, Y.; Yoshioka, H.; Morinaga, R.; Daga, H.; Kurata, T.; Takahashi, T. Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer. Invest. New Drugs 2022 , 40 , 106−114..

Kaira, K.; Tomizawa, Y.; Imai, H.; Sakurai, R.; Matsuura, M.; Yoshii, A.; Ochiai, M.; Kotake, M.; Ebara, T.; Saitoh, J. I.; Sunaga, N.; Minato, K.; Saito, R.; Hisada, T. Phase I study of nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small cell lung cancer. Cancer Chemother. Pharmacol. 2017 , 79 , 165−171..

Hasegawa, T.; Futamura, Y.; Horiba, A.; Yoshida, T.; Suzuki, T.; Kato, T.; Kaito, D.; Ohno, Y.; Iida, T.; Hayashi, S.; Sawa, T. A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non–small-cell lung cancer. J. Radiat. Res. 2016 , 57 , 50−54..

Kawano, Y.; Sasaki, T.; Yamaguchi, H.; Hirano, K.; Horiike, A.; Satouchi, M.; Hosokawa, S.; Morinaga, R.; Komiya, K.; Inoue, K.; Fujita, Y.; Toyozawa, R.; Kimura, T.; Takahashi, K.; Nishikawa, K.; Kishimoto, J.; Nakanishi, Y.; Okamoto, I. Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non–small cell lung cancer. Lung Cancer 2018 , 125 , 136−141..

Sanoff, H. K.; Moon, D. H.; Moore, D. T.; Boles, J.; Bui, C.; Blackstock, W.; O'Neil, B. H.; Subramaniam, S.; McRee, A. J.; Carlson, C.; Lee, M. S.; Tepper, J. E.; Wang, A. Z. Phase I/II trial of nano-camptothecin CRLX101 with capecitabine and radiotherapy as neoadjuvant treatment for locally advanced rectal cancer. Nanomed. Nanotechnol. Biol. Med. 2019 , 18 , 189−195..

Verry, C.; Dufort, S.; Villa, J.; Gavard, M.; Iriart, C.; Grand, S.; Charles, J.; Chovelon, B.; Cracowski, J. L.; Quesada, J. L.; Mendoza, C.; Sancey, L.; Lehmann, A.; Jover, F.; Giraud, J. Y.; Lux, F.; Crémillieux, Y.; McMahon, S.; Pauwels, P. J.; Cagney, D.; Berbeco, R.; Aizer, A.; Deutsch, E.; Loeffler, M.; Le Duc, G.; Tillement, O.; Balosso, J. Theranostic AGuIX nanoparticles as radiosensitizer: a phase I, dose-escalation study in patients with multiple brain metastases (NANO-RAD trial). Radiother. Oncol. 2021 , 160 , 159−165..

Boux, F.; Mercier, A.; Talba, D.; Giraud, J.-Y.; Dufort, S.; Seddik, K.; Grand, S.; Gataleta, M.; Leboucher, A.; Pietras, J.; De Beaumont, O.; Le Duc, G.; Verry, C. Magnetic resonance imaging-based biodistribution of theranostic AGuIX nanoparticles in the NANORAD 2 clinical trial for brain metastases. J. Neurooncol. 2026 , 177 , 91..

Chargari, C.; Maury, P.; Texier, M.; Genestie, C.; Morice, P.; Bockel, S.; Gouy, S.; Ba, M.; Achkar, S.; Lux, F.; Tillement, O.; Dufort, S.; Duc, G. L. E.; Debeaumont, O.; Massard, C.; Maulard, A.; Porcel, E.; Bahleda, R.; Ammari, S.; Morel, D.; Espenel, S.; Pautier, P.; Robert, C.; Deutsch, E. Th eragnostic gadolinium-based nanoparticles safely augment X-ray radiation effects in patients with cervical cancer. ACS Nano 2024 , 18 , 16516−16529..

Thivat, E.; Casile, M.; Moreau, J.; Molnar, I.; Dufort, S.; Seddik, K.; Le Duc, G.; De Beaumont, O.; Loeffler, M.; Durando, X.; Biau, J. Phase I/II study testing the combination of AGuIX nanoparticles with radiochemotherapy and concomitant temozolomide in patients with newly diagnosed glioblastoma (NANO-GBM trial protocol). BMC Cancer 2023 , 23 , 344..

Sapir, E.; Pfeffer, R.; Wygoda, M.; Purim, O.; Levy, A.; Corn, B.; Amitay, Y.; Ohana, P.; Gabizon, A. Pegylated liposomal mitomycin c lipidic prodrug in combination with external beam radiation therapy in patients with advanced cancer: a phase 1B study. Int. J. Radiat. Oncol. Biol. Phys. 2023 , 117 , 64−73..

Le Tourneau, C.; Liem, X.; Nguyen, F.; Deraedt, S.; Salas, S.; Calugaru, V.; Serrahima, M. P.; Wong Hee Kam, S.; Hoffmann, C.; Lesnik, M.; Blanchard, P.; Poissonnet, G.; Bozec, A.; Saada-Bouzid, E.; Jégoux, F.; Castelli, J.; Devisetty, K.; Lelonge, Y.; Jadaud, E.; Houdas, L.; Debard, A.; Vivar, O. I.; Finzi, L.; Serra,A.; Linares, I.; Arranz Obispo, C.; Thariat, J.; Rambeau, A.; Fakhry, N.; Santini, L.; Giralt, J.; Braña García, I.; Barba, M. S.; Gorphe, P.; Helfferich, F.; Herczeg, A.; Papai, Z.; Fijuth, J.; Takácsi-Nagy, Z. Intratumoral radioenhancer nanoparticle NBTXR3 followed by rad iotherapy in head and neck cancer: a phase 1 dose-expansion nonrandomized clinical trial. JAMA Otolaryngol. 2026 , 152 , 284−293..

Le Tourneau, C.; Takácsi-Nagy, Z.; Nuyts, S.; Thureau, S.; Liu, F.; Hoffmann, C.; Hackman, T. G.; Lesnik, M.; Debard, A.; Finzi, L.; Devisetty, K.; Vivar, O. I.; Farber, L. A.; Nguyen, F.; Liem, X.; Natelauri, E.; Psyrri, A.; Burian, M.; Yu, J.; Yom, S. S. Nanoray-312: phase III study of NBTXR3 + radiotherapy ± cetuximab in elderly, platinum-ineligible locally advanced HNSCC. Future Oncol. 2025 , 21 , 1489−1499..

Miller, S. M.; Wang, A. Z. Nanomedicine in chemoradiation. Ther. Deliv. 2013 , 4 , 239−250..

Yi, Q.; Liu, C.; Cui, Y.; Yang, Y.; Li, Y.; Fan, X.; Wu, K. Chemoradiotherapy with paclitaxel liposome plus cisplatin for locally advanced esophageal squamous cell carcinoma: a retrospective analysis. Cancer Med. 2023 , 12 , 6477−6487..

Israel, V. P.; Garcia, A. A.; Roman, L.; Muderspach, L.; Burnett, A.; Jeffers, S.; Muggia, F. M. Phase II study of liposomal doxorubicin in advanced gynecologic cancers. Gynecol. Oncol. 2000 , 78 , 143−147..

Kouloulias, V. E.; Dardoufas, C. E.; Kouvaris, J. R.; Gennatas, C. S.; Polyzos, A. K.; Gogas, H. J.; Sandilos, P. H.; Uzunoglu, N. K.; Malas, E. G.; Vlahos, L. J. Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clin. Cancer. Res. 2002 , 8 , 374−382..

Oh, W. K.; Kaplan, I. D.; Febbo, P.; Prisby, J.; Manola, J.; Kaufman, D. S.; Kantoff, P. W. Neoadjuvant doxil chemotherapy prior to androgen ablation plus radiotherapy for high-risk localized prostate cancer: feasibility and toxicity. Am. J. Clin. Oncol. 2003 , 26 , 312−316..

Koukourakis, M. I.; Koukouraki, S.; Giatromanolaki, A.; Archimandritis, S. C.; Skarlatos, J.; Beroukas, K.; Bizakis, J. G.; Retalis, G.; Karkavitsas, N.; Helidonis, E. S. Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non–small-cell lung cancer and head and neck cancer. J. Clin. Oncol. 1999 , 17 , 3512−3521..

[Wiedenmann, N.; Valdecanas, D.; Hunter, N.; Hyde, S.; Buchholz, T. A.; Milas, L.; Mason, K. A. 130-nmalbumin–bound paclitaxel enhances tumor radiocurability and therapeutic gain. Clin. Cancer. Res . 2007, 13 , 1868−1874..

Madappa, K.; Niu, J. Albumin-bound paclitaxel in solid tumors: clinical development and future directions. Drug Des. Devel. Ther. 2015 , 9 , 3767−3777..

Yardley, D. A. Nab-paclitaxel mechanisms of action and delivery. J. Control. Release 2013 , 170 , 365−372..

Gradishar, W. J.; Tjulandin, S.; Davidson, N.; Shaw, H.; Desai, N.; Bhar, P.; Hawkins, M.; O'Shaughnessy, J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil–based paclitaxel in women with breast cancer. J. Clin. Oncol. 2005 , 23 , 7794−7803..

Frese, K. K.; Neesse, A.; Cook, N.; Bapiro, T. E.; Lolkema, M. P.; Jodrell, D. I.; Tuveson, D. A. Nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov. 2012 , 2 , 260−269..

Zong, Y.; Wu, J.; Shen, K. Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis. Oncotarget 2017 , 8 , 1 7360−17372..

Arscott, W. T.; Nead, K. T.; Bear, A.; Venigalla, S.; Shabason, J.; Lukens, J. N.; Plastaras, J. P.; Wojcieszynski, A.; Metz, J.; O’Hara, M. Concurrent nab-paclitaxel and radiotherapy: novel radiosensitization for borderline resectable or unresectable pancreatic cancer. Am. J. Clin. Oncol. 2021 , 44 , 469−474..

Takahashi, H.; Akita, H.; Ioka, T.; Wada, H.; Tomokoni, A.; Asukai, K.; Ohue, M.; Yano, M.; Ishikawa, O. Phase I trial evaluating the safety of preoperative gemcitabine/nab-paclitaxel with concurrent radiation therapy for borderline resectable pancreatic cancer. Pancreas 2018 , 47 , 1135−1141..

[Tian, X.; Nguyen, M.; Foote, H. P.; Caster, J. M.; Roche, K. C.; Peters, C. G.; Wu, P.; Jayaraman, L.; Garmey, E. G.; Tepper, J. E.; Eliasof, S.; Wang, A. Z. CRLX101, a nanoparticle–drug conjugate containing camptothecin, improves rectal cancer chemoradiotherapy by inhibiting DNA repair and HIF1 α. Cancer Res . 2017, 77 , 112−122..

Du, Y.; Sun, H.; Lux, F.; Xie, Y.; Du, L.; Xu, C.; Zhang, H.; He, N.; Wang, J.; Liu, Y.; Leduc, G.; Doussineau, T.; Ji, K.; Wang, Q.; Lin, Z.; Wang, Y.; Liu, Q.; Tillement, O. Radiosensitization effect of AGuIX, a gadolinium-based nano particle, in nonsmall cell lung cancer. ACS Appl. Mater. Interfaces 2020 , 12 , 56874−56885..

Wang, J.; Liu, M.; Zhang, X.; Wang, X.; Xiong, M.; Luo, D. Stimuli-responsive linkers and their application in molecular imaging. Exploration 2024 , 4 , 20230027..

[Gabizon, A.; Shmeeda, H.; Tahover, E.; Kornev, G.; Patil, Y.; Amitay, Y.; Ohana, P.; Sapir, E.; Zalipsky, S. Development of promitil®, a lipidic prodrug of mitomycin c in PEGylated liposomes: from bench to bedside. Adv. Drug Delivery Rev . 2020, 154−155 , 13−26..

Amitay, Y.; Shmeeda, H.; Patil, Y.; Gorin, J.; Tzemach, D.; Mak, L.; Ohana, P.; Gabizon, A. Pharmacologic studies of a prodrug of mitomycin c in pegylated liposomes (promitil®): high stability in plasma and rapid thiolytic prodrug activation in tissues. Pharm. Res. 2016 , 33 , 686−700..

Tian, X.; Warner, S. B.; Wagner, K. T.; Caster, J. M.; Zhang, T.; Ohana, P.; Gabizon, A. A.; Wang, A. Z. Preclinical evaluation of promitil, a radiation-responsive liposomal formulation of mitomycin c prodrug, in chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 2016 , 96 , 547−555..

Molinaro, M.; Skrodzki, D.; Pan, D. Chemoradiotherapy and nanomedicine: drug mechanisms and delivery systems. Wiley Interdiscip. Rev.:Nanomed. Nanobiotechnol. 2024 , 16 , e1984..

Bienassis, C.; Vivar, O. I.; Hu, Y.; Da silva, J.; Darmon, A.; Marill, J.; Anesary, N. M.; Schmitt, P.; Levy, L.; Welsh, J.; Prezado, Y.; Megnin-Chanet, F.; Paris, S. The radioenhancer NBTXR3: bridging physics and biology to improve radiotherapy outcomes and prime anti-tumor immunity. J. Exp. Clin. Cancer Res. 2025 , 44 , 320..

Wang, R.; Liu, S.; Chen, B.; Xi, M. Recent advances in combination of immunotherapy and chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Cancers (Basel) 2022 , 14 , 5168..

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Effects of Different Nucleating Agents, Annealing and Pre-stretching Process on the Crystallinity and Mechanical Properties of Poly(butylene carbonate)

Multifunctional Polyurethane with High Strength, Toughness, and Self-healing Capacity via Tannic Acid-modified Cellulose Nanocrystals

Polymeric Nanomedicines for Comprehensive Regulation of Tumor Microenvironment

Facile Construction of Hierarchical Polymeric Positive Temperature Coefficient Composites for Improved Reproducibility

Transparent UV-cured Phosphorus/Nitrogen Hybrid Coating for Simultaneously Enhancing Flame Retardancy and Surface Hardness of Polycarbonate

Related Author

No data

Related Institution

No data

⁰