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Fangchinoline-mediated autophagy inhibition amplifies antigen presentation and PD-1 blockade efficacy in lung cancer

Acta Pharmacologica Sinica volume 46, pages 2751–2764 (2025)Cite this article

Abstract

Cancer cells frequently exhibit MHC-I deficiency, impairing immune-mediated cytotoxicity even in the presence of PD-1 checkpoint inhibition. To date, no clinically approved therapies exist that can upregulate MHC-I expression to boost immune responses against cancer cells. Emerging evidence has shown that autophagy plays a role in MHC-I molecule degradation, contributing to reduced recognition of cancer cells by CD8+ T cells. We previously report that fangchinoline, a bisbenzylisoquinoline alkaloid derived from Chinese herb, is a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer. In this study we investigated the modulatory effects of PD-1 blockade combined with fangchinoline on CD8+ T cells within the tumor microenvironment of lung cancer. We showed an inverse correlation between elevated autophagic activity and decreased MHC-I surface expression—a phenomenon often associated with poor clinical efficacies—in various human lung cancer cell lines (NCI-H1299, NCI-H1975, A549, NCI-H1650 and NCI-H446) compared with normal bronchial epithelial cells lung cancer. Knockdown of ATG4 and ATG5 resulted in increased MHC-I expression and enhanced tumor antigen presentation in NCI-H1975, NCI-H1299 and A549 cells. As autophagy receptors were crucial for transporting proteins to autophagosomes for degradation, we sequentially silenced various autophagy receptors and found that NDP52 knockdown specifically restored MHC-I expression, suggesting that NDP52-mediated autophagy might contribute to MHC-I degradation, and autophagy inhibition might enhance immune-mediated cancer cell death. We showed that pretreatment of LLC-OVA cells with the autophagy inhibitor fangchinoline (1.25, 2.5, 5 μM) followed by coculture with CD8+ T cells, dose-dependently enhanced immune killing. In both in vitro and in vivo experiments, we showed that fangchinoline combined with anti-PD-1 therapy significantly increased CD8+ T cell–mediated cytotoxicity. In conclusion, this study highlights NDP52 as a key autophagy receptor involved in MHC-I degradation and provides a new insight into tumor immune evasion. Combining autophagy inhibition with immunotherapy may be a promising therapeutic strategy for anticancer immunity enhancement.

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Fig. 1: Inverse correlation of autophagy upregulation with MHC-I expression in lung cancer.
Fig. 2: NDP52 facilitates MHC-I degradation via autophagy.
Fig. 3: Fangchinoline disrupts autophagic flux in lung cancer cells.
Fig. 4: Fangchinoline significantly increases MHC-I expression and enhances tumor antigen presentation in lung cancer cells.
Fig. 5: Fangchinoline enhances CD8+ T cell–mediated cytotoxicity against lung cancer cells.
Fig. 6: Fangchinoline and PD-1 antibodies synergistically enhance CD8+ T cell immune response against lung cancer cells in vitro.
Fig. 7: Synergistic enhancement of immune-mediated cytotoxicity against lung cancer by fangchinoline and PD-1 antibodies in vivo.
Fig. 8: Mechanism through which fangchinoline enhances T cell immunity via autophagy inhibition in lung cancer cells.

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Data availability

All data generated or analyzed in this study are included in the published article. The raw data used for analysis during this study are available from the corresponding author upon reasonable request.

References

  1. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023;22:40.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. 2023;8:320.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Mamdani H, Matosevic S, Khalid AB, Durm G, Jalal SI. Immunotherapy in lung cancer: current landscape and future directions. Front Immunol. 2022;13:823618.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Qin A, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Cancer Med. 2016;5:2567–78.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hurkmans DP, Kuipers ME, Smit J, Van Marion R, Mathijssen RHJ, Postmus PE, et al. Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients. Cancer Immunol Immunother. 2020;69:771–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Okita R, Maeda A, Shimizu K, Nojima Y, Saisho S, Nakata M. Effect of platinum‑based chemotherapy on the expression of natural killer group 2 member D ligands, programmed cell death‑1 ligand 1 and HLA class I in non‑small cell lung cancer. Oncol Rep. 2019;42:839–48.

    PubMed  CAS  Google Scholar 

  7. Lu ZH, Tu GJ, Fu SL, Shang K, Peng SJ, Chen L, et al. BMI1 induces ubiquitination and protein degradation of Nod-like receptor family CARD domain containing 5 and suppresses human leukocyte antigen class I expression to induce immune escape in non-small cell lung cancer. Kaohsiung J Med Sci. 2022;38:1190–202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Taylor BC, Balko JM. Mechanisms of MHC-I downregulation and role in immunotherapy response. Front Immunol. 2022;13:844866.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Dhatchinamoorthy K, Colbert JD, Rock KL. Cancer immune evasion through loss of MHC class I antigen presentation. Front Immunol. 2021;12:636568.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. White E, Lattime EC, Guo JY. Autophagy regulates stress responses, metabolism, and anticancer immunity. Trends Cancer. 2021;7:778–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Kimmelman AC, White E. Autophagy and tumor metabolism. Cell Metab. 2017;25:1037–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Rangel M, Kong J, Bhatt V, Khayati K, Guo JY. Autophagy and tumorigenesis. FEBS J. 2022;289:7177–98.

    Article  PubMed  CAS  Google Scholar 

  13. Morishita H, Mizushima N. Diverse cellular roles of autophagy. Annu Rev Cell Dev Biol. 2019;35:453–75.

    Article  PubMed  CAS  Google Scholar 

  14. Mathew R, Khor S, Hackett SR, Rabinowitz JD, Perlman DH, White E. Functional role of autophagy-mediated proteome remodeling in cell survival signaling and innate immunity. Mol Cell. 2014;55:916–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;581:100–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Zhan L, Zhang J, Zhang J, Liu X, Zhu S, Shi Y, et al. LC3 and NLRC5 interaction inhibits NLRC5-mediated MHC class I antigen presentation pathway in endometrial cancer. Cancer Lett. 2022;529:37–52.

    Article  PubMed  CAS  Google Scholar 

  17. Wang Y, Zhang Q, Chen Y, Liang CL, Liu H, Qiu F, et al. Antitumor effects of immunity-enhancing traditional Chinese medicine. Biomed Pharmacother. 2020;121:109570.

    Article  PubMed  CAS  Google Scholar 

  18. Gu J, Gui Y, Chen L, Yuan G, Lu HZ, Xu X. Use of natural products as chemical library for drug discovery and network pharmacology. PLoS One. 2013;8:e62839.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yang J, Hu S, Wang C, Song J, Chen C, Fan Y, et al. Fangchinoline derivatives induce cell cycle arrest and apoptosis in human leukemia cell lines via suppression of the PI3K/AKT and MAPK signaling pathway. Eur J Med Chem. 2020;186:111898.

    Article  PubMed  CAS  Google Scholar 

  20. Jung YY, Ha IJ, Um JY, Sethi G, Ahn KS. Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model. J Adv Res. 2022;35:245–57.

    Article  PubMed  CAS  Google Scholar 

  21. Ren Z, Song Y, Xian J, Liao Y, Zhan Y, Zhao T, et al. Identification of Fangchinoline as a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer. Toxicol Appl Pharmacol. 2023;477:116679.

    Article  PubMed  CAS  Google Scholar 

  22. Jin ZJ. About the evaluation of drug combination. Acta Pharmacol Sin. 2004;25:146–7.

    PubMed  CAS  Google Scholar 

  23. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24:560–75.

    Article  PubMed  CAS  Google Scholar 

  24. Gao W, Wang X, Zhou Y, Wang X, Yu Y. Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Sig Transduct Target Ther. 2022;7:196.

    Article  Google Scholar 

  25. Ding J, Wang C, Sun Y, Guo J, Liu S, Cheng Z. Identification of an autophagy-related signature for prognosis and immunotherapy response prediction in ovarian cancer. Biomolecules. 2023;13:339.

  26. Zhu C, Feng X, Tong L, Mu P, Wang F, Quan W, et al. Prediction of acute myeloid leukemia prognosis based on autophagy features and characterization of its immune microenvironment. Front Immunol. 2024;15:1489171.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Gestal‐Mato U, Herhaus L. Autophagy‐dependent regulation of MHC‐I molecule presentation. J Cell Biochem. 2023;125:e30416.

  28. Ye D, Zhou S, Dai X, Xu H, Tang Q, Huang H, et al. Targeting the MHC-I endosomal-lysosomal trafficking pathway in cancer: From mechanism to immunotherapy. Biochim Biophys Acta Rev Cancer. 2024;1879:189161.

    Article  PubMed  CAS  Google Scholar 

  29. Herhaus L, Gestal-Mato U, Eapen VV, Mačinković I, Bailey HJ, Prieto-Garcia C, et al. IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion. Cell. 2024;187:7285–302.e7229.

    Article  PubMed  CAS  Google Scholar 

  30. Yang A, Herter-Sprie G, Zhang H, Lin EY, Biancur D, Wang X, et al. Autophagy sustains pancreatic cancer growth through both cell-autonomous and nonautonomous mechanisms. Cancer Discov. 2018;8:276–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Vargas JNS, Hamasaki M, Kawabata T, Youle RJ, Yoshimori T. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol. 2023;24:167–85.

    Article  PubMed  CAS  Google Scholar 

  32. Fichtner S, Hose D, Engelhardt M, Meissner T, Neuber B, Krasniqi F, et al. Association of antigen-specific T-cell responses with antigen expression and immunoparalysis in multiple myeloma. Clin Cancer Res. 2015;21:1712–21.

    Article  PubMed  CAS  Google Scholar 

  33. Raskov H, Orhan A, Christensen JP, Gögenur I. Cytotoxic CD8+ T cells in cancer and cancer immunotherapy. Br J Cancer. 2021;124:359–67.

    Article  PubMed  CAS  Google Scholar 

  34. Chang HN, Liu BY, Qi YK, Zhou Y, Chen YP, Pan KM, et al. Blocking of the PD-1/PD-L1 Interaction by a D-peptide antagonist for cancer immunotherapy. Angew Chem. 2015;54:11760–4.

    Article  CAS  Google Scholar 

  35. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492–504.

    Article  PubMed  CAS  Google Scholar 

  36. Gu SS, Zhang W, Wang X, Jiang P, Traugh N, Li Z, et al. Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade. Cancer Discov. 2021;11:1524–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Shklovskaya E, Rizos H. MHC class I deficiency in solid tumors and therapeutic strategies to overcome it. Int J Mol Sci. 2021;22:6741.

  38. Denisenko TV, Budkevich IN, Zhivotovsky B. Cell death-based treatment of lung adenocarcinoma. Cell Death Dis. 2018;9:117.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Memmott RM, Wolfe AR, Carbone DP, Williams TM. Predictors of response, progression-free survival, and overall survival in patients with lung cancer treated with immune checkpoint inhibitors. J Thorac Oncol. 2021;16:1086–98.

    Article  PubMed  CAS  Google Scholar 

  40. Malone T, Schäfer L, Simon N, Heavey S, Cuffe S, Finn S, et al. Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer. Pharmacol Ther. 2020;207:107454.

    Article  PubMed  CAS  Google Scholar 

  41. Zhang Q, Zhang Y, Chen Y, Qian J, Zhang X, Yu K. A novel mTORC1/2 Inhibitor (MTI-31) inhibits tumor growth, epithelial-mesenchymal transition, metastases, and improves antitumor immunity in preclinical models of lung cancer. Clin Cancer Res. 2019;25:3630–42.

    Article  PubMed  CAS  Google Scholar 

  42. Xu C, Kim NG, Gumbiner BM. Regulation of protein stability by GSK3 mediated phosphorylation. Cell Cycle. 2009;8:4032–9.

    Article  PubMed  CAS  Google Scholar 

  43. Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer 2021;21:298–312.

    Article  PubMed  CAS  Google Scholar 

  44. Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35:S185–s198.

    Article  PubMed  Google Scholar 

  45. Cornel AM, Mimpen IL, Nierkens S MHC Class I. Downregulation in cancer: underlying mechanisms and potential targets for cancer immunotherapy. Cancers. 2020;12:1760.

  46. Lee JH, Shklovskaya E, Lim SY, Carlino MS, Menzies AM, Stewart A, et al. Transcriptional downregulation of MHC class I and melanoma de-differentiation in resistance to PD-1 inhibition. Nat Commun. 2020;11:1897.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582–7.

    Article  PubMed  CAS  Google Scholar 

  48. Liu X, Bao X, Hu M, Chang H, Jiao M, Cheng J, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature. 2020;588:693–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Zhang W, Lin L, Zhang Y, Zhao T, Zhan Y, Wang H, et al. Dioscin potentiates the antitumor effect of suicide gene therapy in melanoma by gap junction intercellular communication-mediated antigen cross-presentation. Biomed Pharmacother. 2022;150:112973.

    Article  PubMed  CAS  Google Scholar 

  50. Yao CL, Zhang JQ, Li JY, Wei WL, Wu SF, Guo DA. Traditional Chinese medicine (TCM) as a source of new anticancer drugs. Nat Prod Rep. 2021;38:1618–33.

    Article  PubMed  CAS  Google Scholar 

  51. Dong S, Guo X, Han F, He Z, Wang Y. Emerging role of natural products in cancer immunotherapy. Acta Pharm Sin B. 2022;12:1163–85.

    Article  PubMed  CAS  Google Scholar 

  52. Ke M, Zhang Z, Xu B, Zhao S, Ding Y, Wu X, et al. Baicalein and baicalin promote antitumor immunity by suppressing PD-L1 expression in hepatocellular carcinoma cells. Int Immunopharmacol. 2019;75:105824.

    Article  PubMed  CAS  Google Scholar 

  53. Cuyas E, Perez-Sanchez A, Micol V, Menendez JA, Bosch-Barrera J. STAT3-targeted treatment with silibinin overcomes the acquired resistance to crizotinib in ALK-rearranged lung cancer. Cell Cycle. 2016;15:3413–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Yamamoto K, Venida A, Perera RM, Kimmelman AC. Selective autophagy of MHC-I promotes immune evasion of pancreatic cancer. Autophagy. 2020;16:1524–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82104571, 82074070, 82204814), the Natural Science Foundation of Guangdong Province (Grant No. 2022A1515110282), the Science and Technology Plan Project of Guangzhou, China (Grant Nos. 202201011641, 2023A04J2477, 2024A04J10028), the Guangdong Medical Science and Technology Research Foundation (Grant No. A2022488), the Guangdong Provincial Bureau of Traditional Chinese Medicine Research Foundation (Grant Nos. 20222043, 20221115, 20231102), the National Undergraduate Training Programs for Innovation and Entrepreneurship (Grant Nos. 202310572324, 202310572103, 202310572038), and the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (Grant No. pdjh2023b0125).

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  1. These authors contributed equally: Yue Song, Yu-xiao Jiang, Jie-ying Guan

Authors and Affiliations

  1. Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yue Song, Jun-bo Jiang, Man-si Xu, Xue-ying Zhong, Li-na He, Zhen-yang Ren, Yuan Liao, Xiao-yi Liu, Jiang-yong Gu, Ya-fei Shi, Huan-huan Luo & Kun Wang

  2. Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China

    Yue Song

  3. Department of Biochemistry, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yu-xiao Jiang & Jian-yong Xiao

  4. Department of Pathology and Pathophysiology, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Jie-ying Guan, Shan Hu, Ting-xiu Zhao & Kun Wang

  5. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Fang Liu

  6. Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Yan-jun Jiang

  7. The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Wei Guo

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Contributions

Software, Investigation, Methodology, Formal analysis, Visualization, Writing- original draft preparation: YS; Investigation, Methodology, Visualization: YXJ; Methodology, Visualization: FL, JYG; Methodology, Investigation: JBJ, MSX, XYZ; Data curation, Formal analysis: LNH, ZYR, YL, WG; Data curation, Investigation: YJJ; Funding acquisition, Software: SH, XYL; Methodology, Visualization: TXZ, JYG,YFS; Conceptualization, Supervision, Writing-review & editing: HHL; Conceptualization, Formal analysis, Supervision, Writing-review & editing, Funding acquisition: KW; Conceptualization, Funding acquisition, Writing-review & editing: JYX.

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Correspondence to Huan-huan Luo, Kun Wang or Jian-yong Xiao.

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All animal experiments were approved by the Animal Ethics Committee of Guangzhou University of Chinese Medicine (Approval No. 20221027002).

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Song, Y., Jiang, Yx., Guan, Jy. et al. Fangchinoline-mediated autophagy inhibition amplifies antigen presentation and PD-1 blockade efficacy in lung cancer. Acta Pharmacol Sin 46, 2751–2764 (2025). https://doi.org/10.1038/s41401-025-01541-7

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