One phylogenetically conserved mechanism that controls tissue homeostasis and embryonic development is the Wnt/β-catenin pathway. It is aberrantly activated in a variety of cancers, driving malignant transformation, therapeutic resistance, and metastatic dissemination. The pathway regulates tumorigenesis by stabilizing β-catenin, which in turn activates TCF/LEF-mediated transcription of target genes. Uncontrolled cell proliferation, the maintenance of cancer stem cells (CSCs), the epithelial-mesenchymal transition (EMT), and metabolic reprogramming are all facilitated by dysregulated Wnt/β-catenin signaling, while forming an immunosuppressive tumor microenvironment (TME) through impaired dendritic cell (DC) maturation, reduced cytotoxic T cell infiltration, and upregulation of PD-L1. Notably, interactions with other pathways such as PI3K/AKT, Notch, and TGF-β amplify oncogenic signals, complicating therapeutic targeting. Due to the complexity of the pathway, tumor heterogeneity, and compensatory feedback, the clinical translation of Wnt/β-catenin inhibitors remains challenging. Current strategies include targeted inhibitors and combination therapies with immune checkpoint inhibitors (ICIs). Preclinical studies have shown that Wnt pathway blockade can enhance immunotherapy effects by reversing immunosuppression in the TME, while nanotherapeutics and natural compound-based therapies show promise in overcoming chemoresistance. This review integrates current insights into Wnt/β-catenin regulation and its integration with other oncogenic networks, and outlines clinical translational strategies targeting this master regulator, providing new strategies to block tumor progression and improve treatment durability.

1. Vishwakarma M, Piddini E. Outcompeting cancer. Nature Reviews Cancer. 2020;20(3):187-98.

2. Kapoor G, Prakash S, Jaiswal V, Singh AK. Chronic inflammation and Cancer: key pathways and targeted therapies. Cancer Investigation. 2025;43(1):1-23.

3. Glaviano A, Foo AS, Lam HY, Yap KC, Jacot W, Jones RH, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Molecular cancer. 2023;22(1):138.

4. Moon H, Ro SW. MAPK/ERK signaling pathway in hepatocellular carcinoma. Cancers. 2021;13(12):3026.

5. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal transduction and targeted therapy. 2022;7(1):3.

6. Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes & Diseases. 2024;11(2):727-46.

7. Groenewald W, Lund AH, Gay DM. The role of WNT pathway mutations in cancer development and an overview of therapeutic options. Cells. 2023;12(7):990.

8. Dzobo K, Thomford NE, Senthebane DA. Targeting the versatile Wnt/β-catenin pathway in cancer biology and therapeutics: from concept to actionable strategy. Omics: a journal of integrative biology. 2019;23(11):517-38.

9. Sharma A, Mir R, Galande S. Epigenetic regulation of the Wnt/β-catenin signaling pathway in cancer. Frontiers in Genetics. 2021;12:681053.

10. Liu X, Shen X, Zhang J. TRIP13 exerts a cancer‐promoting role in cervical cancer by enhancing Wnt/β‐catenin signaling via ACTN4. Environmental Toxicology. 2021;36(9):1829-40.

11. Wei X, Liao J, Lei Y, Li M, Zhao G, Zhou Y, et al. WSB2 as a target of Hedgehog signaling promoted the malignant biological behavior of Xuanwei lung cancer through regulating Wnt/β-catenin signaling. Translational Cancer Research. 2020;9(12):7394.

12. Guo L, Guo Y-Y, Li B-Y, Peng W-Q, Tang Q-Q. Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. Journal of Biological Chemistry. 2019;294(24):9642-54.

13. Holzem M, Boutros M, Holstein TW. The origin and evolution of Wnt signalling. Nature Reviews Genetics. 2024;25(7):500-12.

14. Haseeb M, Pirzada RH, Ain QU, Choi S. Wnt signaling in the regulation of immune cell and cancer therapeutics. Cells. 2019;8(11):1380.

15. Najafi M, Farhood B, Mortezaee K. Cancer stem cells (CSCs) in cancer progression and therapy. Journal of cellular physiology. 2019;234(6):8381-95.

16. Zhu G-X, Gao D, Shao Z-Z, Chen L, Ding W-J, Yu Q-F. Wnt/β-catenin signaling: Causes and treatment targets of drug resistance in colorectal cancer. Molecular medicine reports. 2021;23(2):105.

17. Stakheev D. Wnt/beta-catenin and mTOR signaling in regulation of T-cell phenotype and cytotoxic activity for adoptive cellular immunotherapy of cancer. 2020.

18. Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/β-catenin signaling pathway in the induction of apoptosis on cancer cells. Pharmaceuticals. 2021;14(9):871.

19. Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cellular and Molecular Life Sciences. 2024;81(1):79.

20. Zhang Y, Yao C, Ju Z, Jiao D, Hu D, Qi L, et al. Krüppel-like factors in tumors: Key regulators and therapeutic avenues. Frontiers in Oncology. 2023;13:1080720.

21. Aghabozorgi AS, Bahreyni A, Soleimani A, Bahrami A, Khazaei M, Ferns GA, et al. Role of adenomatous polyposis coli (APC) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives. Biochimie. 2019;157:64-71.

22. Yang P, Zhu Y, Zheng Q, Meng S, Wu Y, Shuai W, et al. Recent advances of β-catenin small molecule inhibitors for cancer therapy: Current development and future perspectives. European journal of medicinal chemistry. 2022;243:114789.

23. Idrissi YA, Rajabi MR, Beumer JH, Monga SP, Saeed A. Exploring the Impact of the β-Catenin Mutations in Hepatocellular Carcinoma: An In-Depth Review. Cancer Control. 2024;31:10732748241293680.

24. Reyes M, Flores T, Betancur D, Peña-Oyarzún D, Torres VA. Wnt/β-catenin signaling in oral carcinogenesis. International Journal of Molecular Sciences. 2020;21(13):4682.

25. Zhong C, Chen M, Chen Y, Yao F, Fang W. Loss of DSTYK activates Wnt/β-catenin signaling and glycolysis in lung adenocarcinoma. Cell Death & Disease. 2021;12(12):1122.

26. Sun L, Xing J, Zhou X, Song X, Gao S. Wnt/β-catenin signalling, epithelial-mesenchymal transition and crosslink signalling in colorectal cancer cells. Biomedicine & Pharmacotherapy. 2024;175:116685.

27. Pedone E, Marucci L. Role of β-catenin activation levels and fluctuations in controlling cell fate. Genes. 2019;10(2):176.

28. Zhu K, Peng Y, Hu J, Zhan H, Yang L, Gao Q, et al. Metadherin–PRMT5 complex enhances the metastasis of hepatocellular carcinoma through the WNT–β-catenin signaling pathway. Carcinogenesis. 2020;41(2):130-8.

29. Zhao W, Dai S, Yue L, Xu F, Gu J, Dai X, et al. Emerging mechanisms progress of colorectal cancer liver metastasis. Frontiers in endocrinology. 2022;13:1081585.

30. Yu P, Li J, Luo Y, Sun J, Hu Y, Lin B, et al. Mechanistic role of Scutellaria baicalensis Georgi in breast cancer therapy. The American journal of Chinese medicine. 2023;51(02):279-308.

31. Chen J, Wang D, Chen H, Gu J, Jiang X, Han F, et al. TMEM196 inhibits lung cancer metastasis by regulating the Wnt/β-catenin signaling pathway. Journal of Cancer Research and Clinical Oncology. 2023;149(2):653-67.

32. Entezari M, Deldar Abad Paskeh M, Orouei S, Kakavand A, Rezaei S, Sadat Hejazi E, et al. Wnt/β-catenin signaling in lung cancer: association with proliferation, Metastasis, and therapy resistance. Current Cancer Drug Targets. 2024;24(1):94-113.

33. Lou Y-X, Gu J, Zhu L, Sun S-Q, Hao X-L, Chen J-P, et al. TC2N promotes cell proliferation and metastasis in hepatocellular carcinoma by targeting the Wnt/β-catenin signaling pathway. Laboratory Investigation. 2023;103(12):100260.

34. Hagiwara S, Nishida N, Kudo M. Advances in immunotherapy for hepatocellular carcinoma. Cancers. 2023;15(7):2070.

35. Li X, Xiang Y, Li F, Yin C, Li B, Ke X. WNT/β-catenin signaling pathway regulating T cell-inflammation in the tumor microenvironment. Frontiers in immunology. 2019;10:2293.

36. Morita M, Nishida N, Aoki T, Chishina H, Takita M, Ida H, et al. Role of β-catenin activation in the tumor immune microenvironment and immunotherapy of hepatocellular carcinoma. Cancers. 2023;15(8):2311.

37. Xie Q, Li F, Fang L, Liu W, Gu C. The antitumor efficacy of β‐elemene by changing tumor inflammatory environment and tumor microenvironment. BioMed research international. 2020;2020(1):6892961.

38. Mortezaee K. WNT/β-catenin regulatory roles on PD-(L) 1 and immunotherapy responses. Clinical and Experimental Medicine. 2024;24(1):15.

39. Muto S, Enta A, Maruya Y, Inomata S, Yamaguchi H, Mine H, et al. Wnt/β-catenin signaling and resistance to immune checkpoint inhibitors: from non-small-cell lung cancer to other cancers. Biomedicines. 2023;11(1):190.

40. Vallée A, Lecarpentier Y, Vallée J-N. The key role of the WNT/β-catenin pathway in metabolic reprogramming in cancers under normoxic conditions. Cancers. 2021;13(21):5557.

41. Catalano T, D’Amico E, Moscatello C, Di Marcantonio MC, Ferrone A, Bologna G, et al. Oxidative distress induces Wnt/β-catenin pathway modulation in colorectal cancer cells: perspectives on APC retained functions. Cancers. 2021;13(23):6045.

42. Jia L, Peng J, Chen H, Liu Z, Gong J, Sun N, et al. TPTEP1 impedes the reprogramming of fatty acid metabolism in triple negative breast cancer via miR-1343-3p/SIRT3 axis. International Journal of Biological Macromolecules. 2024;280:135792.

43. Le N, Franken P, Fodde R. Tumour–stroma interactions in colorectal cancer: converging on β-catenin activation and cancer stemness. British journal of cancer. 2008;98(12):1886-93.

44. Tsomidis I, Voumvouraki A, Kouroumalis E. Immune Checkpoints and the Immunology of Liver Fibrosis. Livers. 2025;5(1):5.

45. Catalano T, Selvaggi F, Cotellese R, Aceto GM. The Role of Reactive Oxygen Species in Colorectal Cancer Initiation and Progression: Perspectives on Theranostic Approaches. Cancers. 2025;17(5):752.

46. Wu T, Duan X, Hu T, Mu X, Jiang G, Cui S. Effect of endostatin on Wnt pathway of stem-like cells in bladder cancer in tumor microenvironment. Molecular Biology Reports. 2020;47:3937-48.

47. Patel S, Alam A, Pant R, Chattopadhyay S. Wnt signaling and its significance within the tumor microenvironment: novel therapeutic insights. Frontiers in immunology. 2019;10:2872.

48. Ghandadi M, Valadan R, Mohammadi H, Akhtari J, Khodashenas S, Ashari S. Wnt-β-catenin signaling pathway, the achilles' heels of cancer multidrug resistance. Current Pharmaceutical Design. 2019;25(39):4192-207.

49. Saha T, Lukong KE. Breast cancer stem-like cells in drug resistance: a review of mechanisms and novel therapeutic strategies to overcome drug resistance. Frontiers in oncology. 2022;12:856974.

50. Liu L, Zhu H, Liao Y, Wu W, Liu L, Liu L, et al. Inhibition of Wnt/β-catenin pathway reverses multi-drug resistance and EMT in Oct4+/Nanog+ NSCLC cells. Biomedicine & Pharmacotherapy. 2020;127:110225.

51. Selvaggi F, Catalano T, Cotellese R, Aceto GM. Targeting Wnt/β-catenin pathways in primary liver tumours: from microenvironment signaling to therapeutic agents. Cancers. 2022;14(8):1912.

52. Alquati C. A combination of rapamycin, ω3-PUFA docosahexaenoic acid and epigallocatechin-3-gallate for the simultaneous suppression of PI3K/mTOR pathway and Wnt/β-catenin signalling in colorectal carcinogenesis. 2024.

53. Shahcheraghi SH, Tchokonte-Nana V, Lotfi M, Lotfi M, Ghorbani A, Sadeghnia HR. Wnt/beta-catenin and PI3K/Akt/mTOR signaling pathways in glioblastoma: Two main targets for drug design: A review. Current Pharmaceutical Design. 2020;26(15):1729-41.

54. Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, Kim H, et al. Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. The Journal of clinical investigation. 2017;127(1):137-52.

55. Crabtree JS, Singleton CS, Miele L. Notch signaling in neuroendocrine tumors. Frontiers in oncology. 2016;6:94.

56. Zhao H, Ming T, Tang S, Ren S, Yang H, Liu M, et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Molecular cancer. 2022;21(1):144.

57. Iglesias VS. Non-small cell lung cancer: taking it down a NOTCH.

58. Pai SG, Carneiro BA, Mota JM, Costa R, Leite CA, Barroso-Sousa R, et al. Wnt/beta-catenin pathway: modulating anticancer immune response. Journal of hematology & oncology. 2017;10:1-12.

59. Ma H, Chen Q, Zhu F, Zheng J, Li J, Zhang H, et al. Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor. European Journal of Medicinal Chemistry. 2018;149:110-21.

60. Zimmerli D, Cecconi V, Valenta T, Hausmann G, Cantù C, Restivo G, et al. WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma. Oncogene. 2018;37(27):3753-62.

61. Kitagawa T, Matsumoto T, Ohta T, Yoshida T, Saito Y, Nakayama Y, et al. Linderapyrone analogue LPD-01 as a cancer treatment agent by targeting importin7. Journal of Natural Medicines. 2024;78(2):370-81.

62. K Gandhirajan R, J Poll-Wolbeck S, Gehrke I, Kreuzer K-A. Wnt/β-catenin/LEF-1 signaling in chronic lymphocytic leukemia (CLL): a target for current and potential therapeutic options. Current cancer drug targets. 2010;10(7):716-27.

63. Wu C. β-catenin inhibitors ICG-001 and pyrvinium sensitize bortezomib-resistant multiple myeloma cells to bortezomib. Oncology Letters. 2022;24(1):205.

64. Liu H-y, Sun X-j, Xiu S-y, Zhang X-y, Wang Z-q, Gu Y-l, et al. Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers. Acta Pharmacologica Sinica. 2024;45(8):1556-70.

65. Wang C, Yan J, Yin P, Gui L, Ji L, Ma B, et al. β-Catenin inhibition shapes tumor immunity and synergizes with immunotherapy in colorectal cancer. Oncoimmunology. 2020;9(1):1809947.

66. Doo DW, Meza-Perez S, Londoño AI, Goldsberry WN, Katre AA, Boone JD, et al. Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer. Therapeutic advances in medical oncology. 2020;12:1758835920913798.

67. Rialdi A, Duffy M, Scopton AP, Fonseca F, Zhao JN, Schwarz M, et al. WNTinib is a multi-kinase inhibitor with specificity against β-catenin mutant hepatocellular carcinoma. Nature cancer. 2023;4(8):1157-75.

68. Jo S, Im SH, Seo D, Ryu H, Kim SH, Baek D, et al. Low-frequency repetitive magnetic stimulation suppresses neuroblastoma progression by downregulating the Wnt/β-catenin signaling pathway. Bioelectrochemistry. 2022;147:108205.

69. Chen X, Lv X, Gao L, Liu J, Wang W, Guo L, et al. Chalcone derivative CX258 suppresses colorectal cancer via inhibiting the TOP2A/Wnt/β-catenin signaling. Cells. 2023;12(7):1066.

70. Wang J, Wu Z, Peng J, You F, Ren Y, Li X, et al. Multiple roles of baicalin and baicalein in the regulation of colorectal cancer. Frontiers in Pharmacology. 2024;15:1264418.

71. Cao H-H, Liu D-Y, Lai Y-C, Chen Y-Y, Yu L-Z, Shao M, et al. Inhibition of the STAT3 signaling pathway contributes to the anti-melanoma activities of shikonin. Frontiers in pharmacology. 2020;11:748.