TME-responsive Nanocomposite Hydrogel with Targeted Capacity for Enhanced Synergistic Chemoimmunotherapy of MYC-amplified Osteosarcoma

Overview

Journal Bioact Mater

Date 2025 Feb 3

PMID 39897587

Authors

Yichao Ma

Peng Lai

Zhou Sha

Bing Li

Jiangpeng Wu

Xiaojun Zhou

Chuanglong He

Xiaojun Ma

Affiliations

Soon will be listed here.

Abstract

The oncogene MYC is one of the most commonly activated oncogenic proteins in human tumors, with nearly one-fourth of osteosarcoma showing MYC amplification and exhibiting the worst clinical outcomes. The clinical efficacy of single radiotherapy, chemotherapy, and immunotherapy for such osteosarcoma is poor, and the dysregulation of MYC amplification and immune-suppressive tumor microenvironment (TME) may be potential causes of anti-tumor failure. To address the above issues, we developed an injectable TME-responsive nanocomposite hydrogel to simultaneously deliver an effective MYC inhibitor (NHWD-870) and IL11Rα-targeted liposomes containing cisplatin-loaded MnO (Cis/Mn@Lipo-IL11). After administration, NHWD-870 effectively degrades MYC and downregulates CCL2 and IL13 cytokines to trigger M1 type activation of macrophages. Meanwhile, targeted delivery of Cis/Mn@Lipo-IL11 reacts with excess intratumoral GSH to generate Mn and thus inducing excess active oxygen species (ROS) production through Fenton-like reaction, along with cisplatin, thereby inducing immunogenic cell death (ICD) to promote dendritic cell maturation. Through synergistic regulation of MYC and ICD levels, the immune microenvironment was reshaped to enhance immune infiltration. In the osteosarcoma-bearing model, the nanocomposite hydrogel significantly enhanced tumor T cell infiltration, induced effective anti-tumor immunity and attenuated lung metastasis. Therefore, our results reveal a powerful strategy for targeted combination therapy of MYC-amplified osteosarcoma.

References

Dhanasekaran R, Baylot V, Kim M, Kuruvilla S, Bellovin D, Adeniji N . and cooperate to drive metastasis by eliciting crosstalk between cancer and innate immunity. Elife. 2020; 9. PMC: 6959993. DOI: 10.7554/eLife.50731. View

Dhanasekaran R, Deutzmann A, Mahauad-Fernandez W, Hansen A, Gouw A, Felsher D . The MYC oncogene - the grand orchestrator of cancer growth and immune evasion. Nat Rev Clin Oncol. 2021; 19(1):23-36. PMC: 9083341. DOI: 10.1038/s41571-021-00549-2. View

Gao F, Li X, Xu K, Wang R, Guan X . c-MYC mediates the crosstalk between breast cancer cells and tumor microenvironment. Cell Commun Signal. 2023; 21(1):28. PMC: 9887805. DOI: 10.1186/s12964-023-01043-1. View

Wang Y, Ju L, Wang G, Qian K, Jin W, Li M . DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nat Commun. 2023; 14(1):2421. PMC: 10140023. DOI: 10.1038/s41467-023-38160-x. View

Zhang R, Shen Y, Zhang Q, Feng X, Liu X, Huo X . TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer. Cell Death Dis. 2023; 14(12):850. PMC: 10733312. DOI: 10.1038/s41419-023-06383-x. View

Zhao Z, Dong S, Liu Y, Wang J, Ba L, Zhang C . Tumor Microenvironment-Activable Manganese-Boosted Catalytic Immunotherapy Combined with PD-1 Checkpoint Blockade. ACS Nano. 2022; 16(12):20400-20418. DOI: 10.1021/acsnano.2c06646. View

Du L, He H, Xiao Z, Xiao H, An Y, Zhong H . GSH-Responsive Metal-Organic Framework for Intratumoral Release of NO and IDO Inhibitor to Enhance Antitumor Immunotherapy. Small. 2022; 18(15):e2107732. DOI: 10.1002/smll.202107732. View

Zhang C, Wei S, Dai S, Li X, Wang H, Zhang H . The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development. J Immunother Cancer. 2023; 11(5). PMC: 10230994. DOI: 10.1136/jitc-2022-006230. View

Zimmerli D, Brambillasca C, Talens F, Bhin J, Linstra R, Romanens L . MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling. Nat Commun. 2022; 13(1):6579. PMC: 9630413. DOI: 10.1038/s41467-022-34000-6. View

10.

See Y, Chen K, Fullwood M . overexpression leads to increased chromatin interactions at super-enhancers and MYC binding sites. Genome Res. 2022; 32(4):629-642. PMC: 8997345. DOI: 10.1101/gr.276313.121. View

11.

Duffy M, OGrady S, Tang M, Crown J . MYC as a target for cancer treatment. Cancer Treat Rev. 2021; 94:102154. DOI: 10.1016/j.ctrv.2021.102154. View

12.

Sha Z, Yang S, Fu L, Geng M, Gu J, Liu X . Manganese-doped gold core mesoporous silica particles as a nanoplatform for dual-modality imaging and chemo-chemodynamic combination osteosarcoma therapy. Nanoscale. 2021; 13(9):5077-5093. DOI: 10.1039/d0nr09220g. View

13.

Lewis V . IL-11Rα: a novel target for the treatment of osteosarcoma. Adv Exp Med Biol. 2014; 804:285-9. DOI: 10.1007/978-3-319-04843-7_15. View

14.

Yaghmur A, Ostergaard J, Mu H . Lipid nanoparticles for targeted delivery of anticancer therapeutics: Recent advances in development of siRNA and lipoprotein-mimicking nanocarriers. Adv Drug Deliv Rev. 2023; 203:115136. DOI: 10.1016/j.addr.2023.115136. View

15.

Lourenco C, Resetca D, Redel C, Lin P, MacDonald A, Ciaccio R . MYC protein interactors in gene transcription and cancer. Nat Rev Cancer. 2021; 21(9):579-591. DOI: 10.1038/s41568-021-00367-9. View

16.

Moujalled D, Southon A, Saleh E, Brinkmann K, Ke F, Iliopoulos M . BH3 mimetic drugs cooperate with Temozolomide, JQ1 and inducers of ferroptosis in killing glioblastoma multiforme cells. Cell Death Differ. 2022; 29(7):1335-1348. PMC: 9287558. DOI: 10.1038/s41418-022-00977-2. View

17.

Xie P, Jin Q, Zhang L, Zhang H, Montesdeoca N, Karges J . Endowing Pt(IV) with Perfluorocarbon Chains and Human Serum Albumin Encapsulation for Highly Effective Antitumor Chemoimmunotherapy. ACS Nano. 2024; 18(21):13683-13695. DOI: 10.1021/acsnano.4c01352. View

18.

Hu R, Hou H, Li Y, Zhang M, Li X, Chen Y . Combined BET and MEK Inhibition synergistically suppresses melanoma by targeting YAP1. Theranostics. 2024; 14(2):593-607. PMC: 10758063. DOI: 10.7150/thno.85437. View

19.

Jiang Y, Wang J, Sun M, Zuo D, Wang H, Shen J . Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment. Nat Commun. 2022; 13(1):7207. PMC: 9684515. DOI: 10.1038/s41467-022-34689-5. View

20.

Liu J, Zhan J, Zhang Y, Huang L, Yang J, Feng J . Ultrathin Clay Nanoparticles-Mediated Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy. Adv Mater. 2023; 36(9):e2309562. DOI: 10.1002/adma.202309562. View