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Dendritic cell-liposome conjugates reverse immunosuppressive tumor microenvironment for inhibiting colitis-associated colorectal cancer

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

The progression of colitis-associated cancer (CAC) is strongly associated with bone marrow-derived immunosuppressive cells (MDSCs). Although CAC could be suppressed by inducing MDSCs apoptosis, the immunosuppressive tumor microenvironment (TME) maintains immune homeostasis by upregulating M2-type tumor-associated macrophages (TAMs), thus leading to adaptive immune tolerance. Herein, we develop a dendritic cell (DC)-liposome conjugate to reverse immunosuppressive TME, showing remarkable efficiency against colorectal cancer. The DC-liposome conjugate is fabricated by conjugating resolvin E1-loaded liposomes with Fas ligand-transfected DCs, which eliminates tumor-infiltrated Fas+ MDSCs and enhances TAM phagocytosis in tumors. It shows significant therapeutic effects in preclinical CAC models and alleviates severe colitis when combined with immune checkpoint inhibitors. This study provides a feasible and customized cell-drug conjugate to overcome immunosuppressive TME for enhancing CAC immunotherapy.

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Fig. 1: Preparation and characterization of FasL-DC-Lipo.
Fig. 2: Biological functions and in vivo distribution of FasL-DC-Lipo.
Fig. 3: Antitumor immune responses in AOM/DSS-induced murine CAC.
Fig. 4: Treatment efficacy of FasL-DC-Lipo against DSS/AOM-induced murine CAC.
Fig. 5: In vivo safety of FasL-DC-Lipo after intraperitoneal injection.
Fig. 6: Treatment efficacy of FasL-DC-Lipo in combination with immune checkpoint inhibitors.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. The raw datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

References

  1. Nunes L, Li F, Wu M, Luo T, Hammarström K, Torell E, et al. Prognostic genome and transcriptome signatures in colorectal cancers. Nature. 2024;633:137–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Levi-Galibov O, Lavon H, Wassermann-Dozorets R, Pevsner-Fischer M, Mayer S, Wershof E, et al. Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer. Nat Commun. 2020;11:6245.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Shah SC, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology. 2022;162:715–30.

    Article  PubMed  Google Scholar 

  4. Robles AI, Traverso G, Zhang M, Roberts NJ, Khan MA, Joseph C, et al. Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology. 2016;150:931–43.

    Article  PubMed  CAS  Google Scholar 

  5. Dan WY, Zhou GZ, Peng LH, Pan F. Update and latest advances in mechanisms and management of colitis-associated colorectal cancer. World J Gastrointest Oncol. 2023;15:1317–31.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schmitt M, Greten FR. The inflammatory pathogenesis of colorectal cancer. Nat Rev Immunol. 2021;21:653–67.

    Article  PubMed  CAS  Google Scholar 

  7. Baker AM, Cross W, Curtius K, Al Bakir I, Choi CR, Davis HL, et al. Evolutionary history of human colitis-associated colorectal cancer. Gut. 2019;68:985–95.

    Article  PubMed  CAS  Google Scholar 

  8. Ocansey DKW, Qiu W, Wang J, Yan Y, Qian H, Zhang X, et al. The achievements and challenges of mesenchymal stem cell-based therapy in inflammatory bowel disease and its associated colorectal cancer. Stem Cells Int. 2020;2020:7819824.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang K, Wang Y, Yin K. Role played by MDSC in colitis-associated colorectal cancer and potential therapeutic strategies. J Cancer Res Clin Oncol. 2024;150:243.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Segal AW. Studies on patients establish Crohn’s disease as a manifestation of impaired innate immunity. J Intern Med. 2019;286:373–88.

    Article  PubMed  CAS  Google Scholar 

  11. Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol. 2017;8:86.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen Z, Zhang X, Xing Z, Lv S, Huang L, Liu J, et al. OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment. Oncogene. 2022;41:3131–50.

    Article  PubMed  CAS  Google Scholar 

  13. Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol. 2024;21:147–64.

    Article  PubMed  CAS  Google Scholar 

  14. Mei Y, Zhu Y, Yong KSM, Hanafi ZB, Gong H, Liu Y, et al. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment. Cell Rep. 2024;43:113835.

    Article  PubMed  CAS  Google Scholar 

  15. Li S, Xu F, Ren X, Tan L, Fu C, Wu Q, et al. H2S-reactivating antitumor immune response after microwave thermal therapy for long-term tumor suppression. ACS Nano. 2023;17:19242–53.

    Article  PubMed  CAS  Google Scholar 

  16. Xia Y, Rao L, Yao H, Wang Z, Ning P, Chen X. Engineering macrophages for cancer immunotherapy and drug delivery. Adv Mater. 2020;32:2002054.

    Article  CAS  Google Scholar 

  17. Cheng S, Li Z, Gao R, Xing B, Gao Y, Yang Y, et al. A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells. Cell. 2021;184:792–809.

    Article  PubMed  CAS  Google Scholar 

  18. Zhang L, Li Z, Skrzypczynska KM, Fang Q, Zhang W, O’Brien SA, et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell. 2020;181:442–59.

    Article  PubMed  CAS  Google Scholar 

  19. Xiao CX, Wang HH, Shi Y, Li P, Liu YP, Ren JL, et al. Distribution of bone-marrow-derived endothelial and immune cells in a murine colitis-associated colorectal cancer model. PLoS One. 2013;8:e73666.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Zundler S, Günther C, Kremer AE, Zaiss MM, Rothhammer V, Neurath MF. Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation. Nat Rev Gastroenterol Hepatol. 2023;20:50–64.

    Article  PubMed  Google Scholar 

  21. Herová M, Schmid M, Gemperle C, Hersberger M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J Immunol. 2015;194:2330–7.

    Article  PubMed  Google Scholar 

  22. Sinha P, Chornoguz O, Clements VK, Artemenko KA, Zubarev RA, Ostrand-Rosenberg S. Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL. Blood. 2011;117:5381–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J Biol Chem. 2010;285:3451–61.

    Article  PubMed  CAS  Google Scholar 

  24. De Matteis R, Flak MB, Gonzalez-Nunez M, Austin-Williams S, Palmas F, Colas RA, et al. Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer. Sci Adv. 2022;8:abl5420.

    Article  Google Scholar 

  25. Dooling LJ, Andrechak JC, Hayes BH, Kadu S, Zhang W, Pan R, et al. Cooperative phagocytosis of solid tumours by macrophages triggers durable anti-tumour responses. Nat Biomed Eng. 2023;7:1081–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Yan G, Zhao H, Zhang Q, Zhou Y, Wu L, Lei J, et al. A RIPK3-PGE2 circuit mediates myeloid-derived suppressor cell-potentiated colorectal carcinogenesis. Cancer Res. 2018;78:5586–99.

    Article  PubMed  CAS  Google Scholar 

  27. Hirano T, Hirayama D, Wagatsuma K, Yamakawa T, Yokoyama Y, Nakase H. Immunological mechanisms in inflammation-associated colon carcinogenesis. Int J Mol Sci. 2020;21:3062.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, et al. Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases. 2019;7:405–18.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases. 2024;12:1050–62.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lo BC, Kryczek I, Yu J, Vatan L, Caruso R, Matsumoto M, et al. Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade-associated colitis via Fcγ receptors. Science. 2024;383:62–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Hailemichael Y, Johnson DH, Abdel-Wahab N, Foo WC, Bentebibel SE, Daher M, et al. Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 2022;40:509–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank the National Center for Protein Science Shanghai for the platform of Fortessa flow cytometer, Leica TCS SP8 confocal microscope and 200 kV TEM. We are grateful to Y. Wang for FACS training, F. Liu for training in using confocal microscopy and J. Duan for operating 200 kV TEM (TF20, FEI). Financial supports from National Key R&D Program of China (2022YFC3401404), National Natural Science Foundation of China (32170935), Strategic Priority Research Program of the Chinese Academy of Grant (XDC0290302), Science and Technology Commission of Shanghai Municipality (24J22800600) and Shandong Laboratory Program (SYS202205) are gratefully acknowledged.

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Author notes

  1. These authors contributed equally: Wen-zhe Yi, Xin-di Qian

Authors and Affiliations

  1. State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen-zhe Yi, Xin-di Qian, Xiao-xuan Xu, Dan Yan, Zhi-wen Zhao & Ya-ping Li

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Wen-zhe Yi, Xiao-xuan Xu, Zhi-wen Zhao & Ya-ping Li

  3. Department of Medical Ultrasound and Center of Minimally Invasive Treatment for Tumor, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, School of Medicine Tongji University, Shanghai, 200072, China

    Xin-di Qian

  4. Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Rong Pu & Ya-ping Li

  5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264000, China

    Ya-ping Li

  6. Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China

    Dang-ge Wang

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Contributions

WZY and DGW conceived and designed the project, analyzed and interpreted data, and wrote and edited the manuscript; WZY carried out the characterization of the system in vitro and in vivo; WZY and DGW conducted proteomics and analyzed data; WZY, XDQ, XXX, RP, DY and ZWZ contributed to the animal experiment. DGW and YPL supervised the research; All authors discussed the results and reviewed the manuscript.

Corresponding authors

Correspondence to Ya-ping Li or Dang-ge Wang.

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Yi, Wz., Qian, Xd., Xu, Xx. et al. Dendritic cell-liposome conjugates reverse immunosuppressive tumor microenvironment for inhibiting colitis-associated colorectal cancer. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01614-7

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