Esophageal cancer is a highly prevalent malignant tumor of the digestive system. Autophagy exerts dual tumor-suppressive and tumor-promoting regulatory effects in the progression of esophageal cancer, serving as an important target for tumor-targeted intervention. Existing studies have confirmed that active constituents of traditional Chinese medicine (TCM) can regulate autophagy in esophageal cancer cells; however, the relevant mechanisms lack systematic summarization. This review describes the dual biological functions and molecular regulatory mechanisms of autophagy in esophageal cancer. It further summarizes recent advances regarding the autophagy-modulating effects of TCM active constituents and herbal formulas along four key regulatory axes: mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), and autophagosome-lysosome fusion. Two intervention modes, including inducing lethal autophagy and counteracting protective autophagy, are highlighted. Major limitations, including non-standard autophagic flux assays and insufficient in vivo translational research, are also addressed, aiming to provide theoretical support for autophagy-targeted therapy of esophageal cancer and the research and development of TCM active constituents.

1. BrayF, LaversanneM, SungH, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

2. QiL, SunM, LiuW, et al. Global esophageal cancer epidemiology in 2022 and predictions for 2050: a comprehensive analysis and projections based on GLOBOCAN data[J]. Chin Med J (Engl), 2024, 137(24): 3108-3116. DOI: 10.1097/CM9.0000000000003420.

3. YangH, WangF, HallemeierCL, et al. Oesophageal cancer[J]. Lancet, 2024, 404(10466): 1991-2005. DOI: 10.1016/S0140-6736(24)02226-8.

4. KlionskyDJ, Abdel-AzizAK, AbdelfatahS, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)[J]. Autophagy, 2021, 17(1): 1-382. DOI: 10.1080/15548627.2020.1797280.

5. ZhouS, SunX, JinZ, et al. The role of autophagy in initiation, progression, TME modification, diagnosis, and treatment of esophageal cancers[J]. Crit Rev Oncol Hematol, 2022, 175: 103702. DOI: 10.1016/j.critrevonc.2022.103702.

6. ZhangD, WuJ, WangH, et al. Systematic review and network Meta-analysis comparing Chinese herbal injections with chemotherapy for treating patients with esophageal cancer[J]. J Int Med Res, 2020, 48(1): 300060519898336. DOI: 10.1177/0300060519898336.

7. HuangJ, FanT, RongY, et al. Efficacy of Aidi injection combined with chemotherapy, radiotherapy or chemoradiotherapy for unresectable esophageal cancer treatment: a Meta-analysis and systematic review of 29 randomized controlled trials based on Asian populations (China)[J]. Eur J Clin Pharmacol, 2023, 79(6): 707-722. DOI: 10.1007/s00228-023-03493-5.

8. ZhouW, HuangZ, WuC, et al. Investigation on the clinical efficacy and mechanism of compound kushen injection in treating esophageal cancer based on multi-dimensional network Meta-analysis and in vitro experiment[J]. J Ethnopharmacol, 2021, 279: 114386. DOI: 10.1016/j.jep.2021.114386.

9. da SilvaMF, LinsAA, GomesMC, et al. Anticancer drug discovery from natural compounds targeting PI3K/AKT/mTOR signaling pathway[J]. Curr Med Chem, 2025, 32(24): 4859-4887. DOI: 10.2174/0109298673325229240928040758.

10. GalluzziL, VitaleI, AaronsonSA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018[J]. Cell Death Differ, 2018, 25(3): 486-541. DOI: 10.1038/s41418-017-0012-4.

11. DikicI, ElazarZ. Mechanism and medical implications of mammalian autophagy[J]. Nat Rev Mol Cell Biol, 2018, 19(6): 349-364. DOI: 10.1038/s41580-018-0003-4.

12. GuoY, LiuY, YangH, et al. Associations of porphyromonas gingivalis infection and low Beclin1 expression with clinicopathological parameters and survival of esophageal squamous cell carcinoma patients[J]. Pathol Oncol Res, 2021, 27: 1609976. DOI: 10.3389/pore.2021.1609976.

13. SalehiS, Mottaghi-DastjerdiN, ShahbaziB, et al. Autophagy-centered gene networks reveal prognostic biomarkers and therapeutic targets in esophageal cancer[J]. Discov Oncol, 2026, 17(1): 1071. DOI: 10.1007/s12672-026-04783-x.

14. O'DonovanTR, O'SullivanGC, McKennaSL. Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics[J]. Autophagy, 2011, 7(5): 509-524. DOI: 10.4161/auto.7.6.15066.

15. QiuH, SongH, LuoM, et al. Dysfunction of apoptosis and autophagy correlates with local recurrence in esophageal squamous cell carcinoma after definitive chemoradiation[J]. Cancer Cell Int, 2021, 21(1): 466. DOI: 10.1186/s12935-021-02171-9.

16. SaxtonRA, SabatiniDM. mTOR Signaling in growth, metabolism, and disease[J]. Cell, 2017, 169(2): 361-371. DOI: 10.1016/j.cell.2017.03.035.

17. KimJ, KunduM, ViolletB, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1[J]. Nat Cell Biol, 2011, 13(2): 132-141. DOI: 10.1038/ncb2152.

18. LinSC, HardieDG. AMPK: sensing glucose as well as cellular energy status[J]. Cell Metab, 2018, 27(2): 299-313. DOI: 10.1016/j.cmet.2017.10.009.

19. PengY, TaoY, LiuL, et al. Crosstalk among reactive oxygen species, autophagy and metabolism in myocardial ischemia and reperfusion stages[J]. Aging Dis, 2024, 15(3): 1075-1107. DOI: 10.14336/AD.2023.0823-4.

20. KwonJ, LeeSR, YangKS, et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors[J]. Proc Natl Acad Sci U S A, 2004, 101(47): 16419-16424. DOI: 10.1073/pnas.0407396101.

21. Scherz-ShouvalR, ShvetsE, FassE, et al. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4[J]. EMBO J, 2007, 26(7): 1749-1760. DOI: 10.1038/sj.emboj.7601623.

22. NakamuraS, YoshimoriT. New insights into autophagosome-lysosome fusion[J]. J Cell Sci, 2017, 130(7): 1209-1216. DOI: 10.1242/jcs.196352.

23. ZhaoYG, ZhangH. Autophagosome maturation: an epic journey from the ER to lysosomes[J]. J Cell Biol, 2019, 218(3): 757-770. DOI: 10.1083/jcb.201810099.

24. ItakuraE, Kishi-ItakuraC, MizushimaN. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes[J]. Cell, 2012, 151(6): 1256-1269. DOI: 10.1016/j.cell.2012.11.001.

25. SaftigP, BeertsenW, EskelinenEL. LAMP-2: a control step for phagosome and autophagosome maturation[J]. Autophagy, 2008, 4(4): 510-512. DOI: 10.4161/auto.5724.

26. JianF, WangS, TianW, et al. Deacetylated SNAP47 recruits HOPS to facilitate autophagosome-lysosome fusion independent of STX17[J]. Nat Commun, 2025, 16(1): 543. DOI: 10.1038/s41467-025-55906-x.

27. SettembreC, FraldiA, MedinaDL, et al. Signals from the lysosome: a control centre for cellular clearance and energy metabolism[J]. Nat Rev Mol Cell Biol, 2013, 14(5): 283-296. DOI: 10.1038/nrm3565.

28. 侯敏杰, 林淑璇, 吕洋. 苦参碱对食管癌Eca-109细胞自噬的影响及作用机制[J]. 新乡医学院学报, 2023, 40(10): 901-908.HouMJ, LinSX, LyuY. Effects and mechanism of matrine on autophagy in esophageal cancer Eca-109 cells[J]. Journal of Xinxiang Medical University, 2023, 40(10): 901-908. DOI: 10.7683/xxyxyxb.2023.10.001.

29. 刘丰熙, 李刚, 李秀娟, 等. 苦参碱通过抑制PI3K/Akt/mTOR信号通路诱导食管癌Ec109细胞自噬[J]. 西安交通大学学报(医学版), 2020, 41(03): 468-472.LiuFX, LiG, LiXJ, et al. Matrine induces autophagy in esophageal cancer Ec109 cells by inhibiting PI3K/Akt/mTOR signaling pathway[J]. Journal of Xi'an Jiaotong University (Medical Sciences), 2020, 41(3): 468-472. DOI: 10.7652/jdyxb202003028.

30. LiuB, WuP, LiX, et al. Matrine inhibits proliferation and migration of esophageal cancer cells by regulating autophagy via the PI3K/Akt/mTOR pathway[J]. Tohoku J Exp Med, 2025. DOI: 10.1620/tjem.2025.J155.

31. LiuH, ZhaoJ, FuR, et al. The ginsenoside Rk3 exerts anti-esophageal cancer activity in vitro and in vivo by mediating apoptosis and autophagy through regulation of the PI3K/Akt/mTOR pathway[J]. PLoS One, 2019, 14(5): e0216759. DOI: 10.1371/journal.pone.0216759.

32. DengL, WuX, ZhuX, et al. Combination effect of curcumin with docetaxel on the PI3K/AKT/mTOR pathway to induce autophagy and apoptosis in esophageal squamous cell carcinoma[J]. Am J Transl Res, 2021, 13(1): 57-72. https://pubmed.ncbi.nlm.nih.gov/33527008/.

33. TianY, ZhangJ, YuY, et al. Multi-components in modified Tongyou decoction targeting Akt/mTOR to modulate esophageal cancer cell autophagy via network pharmacology integrated with experimental verification[J]. Clin Exp Gastroenterol, 2025, 18: 305-325. DOI: 10.2147/CEG.S560771.

34. JuJ, XuN, LiB, et al. Triptonide facilitates autophagy-mediated apoptosis in esophageal squamous cell carcinoma by targeting the AMPK-mTOR-ULK1 axis[J]. Acta Biochim Biophys Sin (Shanghai), 2025, 57(10): 1611-1624. DOI: 10.3724/abbs.2025056.

35. ZhangJ, GuoJ, GuB, et al. Shikonin induces autophagy and apoptosis in esophageal cancer EC9706 cells by regulating the AMPK/mTOR/ULK axis[J]. Anal Cell Pathol (Amst), 2024, 2024: 7752299. DOI: 10.1155/2024/7752299.

36. MaQ, LiaoH, XuL, et al. Autophagy-dependent cell cycle arrest in esophageal cancer cells exposed to dihydroartemisinin[J]. Chin Med, 2020, 15: 37. DOI: 10.1186/s13020-020-00318-w.

37. LeeNR, MengRY, RahSY, et al. Reactive oxygen species-mediated autophagy by ursolic acid inhibits growth and metastasis of esophageal cancer cells[J]. Int J Mol Sci, 2020, 21(24): 9409. DOI: 10.3390/ijms21249409.

38. PengY, ZhouT, WangS, et al. Dehydrocostus lactone inhibits the proliferation of esophageal cancer cells in vivo and in vitro through ROS-mediated apoptosis and autophagy[J]. Food Chem Toxicol, 2022, 170: 113453. DOI: 10.1016/j.fct.2022.113453.

39. LiuZ, HuangK, HuangH, et al. Isoquercitrin suppresses esophageal squamous cell carcinoma (ESCC) by inducing excessive autophagy and promoting apoptosis via the AKT/mTOR signaling pathway[J]. Antioxidants (Basel), 2025, 14(6): 694. DOI: 10.3390/antiox14060694.

40. ZhengK, LiY, WangS, et al. Inhibition of autophagosome-lysosome fusion by ginsenoside Ro via the ESR2-NCF1-ROS pathway sensitizes esophageal cancer cells to 5-fluorouracil-induced cell death via the CHEK1-mediated DNA damage checkpoint[J]. Autophagy, 2016, 12(9): 1593-1613. DOI: 10.1080/15548627.2016.1192751.

41. ShaoCS, ZhouXH, ZhengXX, et al. Ganoderic acid D induces synergistic autophagic cell death except for apoptosis in ESCC cells[J]. J Ethnopharmacol, 2020, 262: 113213. DOI: 10.1016/j.jep.2020.113213.

42. WeiS, WangJ, ZhangZ, et al. A novel autophagy inhibitor p-hydroxylcinnamaldehyde suppresses esophageal squamous cell carcinoma by targeting LDHA phosphorylation-mediated metabolic reprogramming[J]. Research (Wash D C), 2026, 9: 1070. DOI: 10.34133/research.1070.