An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer

Merve Aykaç

An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer

Abstract

The Hippo signaling pathway is a highly conserved signaling cascade that plays a critical role in the regulation of cellular functions through its interaction with multiple signaling pathways. Beyond its role in normal cellular processes, it significantly contributes to tumor progression, including tumor initiation, invasion, and metastasis. Core components of the Hippo pathway, particularly YAP/TAZ and TEAD, act in concert with other signaling pathways to drive tumor progression and shape the tumor microenvironment. The PD-1/PD-L1 axis, recognized as a key immune checkpoint pathway, facilitates tumor immune evasion by suppressing T cell responses in tumor cells. Importantly, the principal components of the Hippo pathway, together with immune checkpoint regulators, modulate the tumor microenvironment by influencing T cell function, myeloid-derived suppressor cell (MDSC) activity, and macrophage polarization and accumulation. Given that inhibition of the Hippo signaling pathway can suppress the expression of immune checkpoint molecules such as PD-L1, it represents a promising therapeutic target in anticancer research. This review aims to systematically evaluate the relationship between Hippo-YAP/TAZ signaling and PD-L1 across different tumor types.

Keywords

References

Agata, Y., Kawasaki, A., Nishimura, H., Ishida, Y., Tsubat, T., Yagita, H., & Honjo, T. (1996). Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. International Immunology, 8(5), 765–772.
Bisso, A., Filipuzzi, M., Gamarra Figueroa, G. P., Brumana, G., Biagioni, F., Doni, M., Ceccotti, G., Tanaskovic, N., Morelli, M. J., & Pendino, V. (2020). Cooperation between MYC and β‐catenin in liver tumorigenesis requires Yap/Taz. Hepatology, 72(4), 1430–1443.
Calses, P. C., Crawford, J. J., Lill, J. R., & Dey, A. (2019). Hippo pathway in cancer: aberrant regulation and therapeutic opportunities. Trends in Cancer, 5(5), 297–307.
Chan, L. H., Wang, W., Yeung, W., Deng, Y., Yuan, P., & Mak, K. K. (2014). Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. Oncogene, 33(40), 4857–4866.
Chen, C., Du, Y., Nie, R., Wang, S., Wang, H., & Li, P. (2025). Notch signaling in cancers: mechanism and potential therapy. Frontiers in Cell and Developmental Biology, 13, 1542967.
Chen, N., Fang, W., Zhan, J., Hong, S., Tang, Y., Kang, S., Zhang, Y., He, X., Zhou, T., & Qin, T. (2015). Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC: implication for optional immune targeted therapy for NSCLC patients with EGFR mutation. Journal of Thoracic Oncology, 10(6), 910–923.
Cordenonsi, M., Zanconato, F., Azzolin, L., Forcato, M., Rosato, A., Frasson, C., Inui, M., Montagner, M., Parenti, A. R., & Poletti, A. (2011). The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell, 147(4), 759–772.
Fernandez-L, A., Squatrito, M., Northcott, P., Awan, A., Holland, E. C., Taylor, M. D., Nahlé, Z., & Kenney, A. M. (2012). Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene, 31(15), 1923–1937.

Fu, M., Hu, Y., Lan, T., Guan, K.-L., Luo, T., & Luo, M. (2022). The Hippo signalling pathway and its implications in human health and diseases. Signal Transduction and Targeted Therapy, 7(1), 376.
Han, Y., Liu, D., & Li, L. (2021). Increased expression of TAZ and associated upregulation of PD-L1 in cervical cancer. Cancer Cell International, 21(1), 592.
He, J., Hu, Y., Hu, M., & Li, B. (2015). Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Scientific Reports, 5(1), 13110.
Hsu, P.-C., Jablons, D. M., Yang, C.-T., & You, L. (2019). Epidermal growth factor receptor (EGFR) pathway, yes-associated protein (YAP) and the regulation of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). International Journal of Molecular Sciences, 20(15), 3821.
Ishida, M., Iwai, Y., Tanaka, Y., Okazaki, T., Freeman, G. J., Minato, N., & Honjo, T. (2002). Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunology Letters, 84(1), 57–62.
Janse van Rensburg, H. J., Azad, T., Ling, M., Hao, Y., Snetsinger, B., Khanal, P., Minassian, L. M., Graham, C. H., Rauh, M. J., & Yang, X. (2018). The Hippo pathway component TAZ promotes immune evasion in human cancer through PD-L1. Cancer Research, 78(6), 1457–1470.
Kim, M. H., Kim, C. G., Kim, S.-K., Shin, S. J., Choe, E. A., Park, S.-H., Shin, E.-C., & Kim, J. (2018). YAP-induced PD-L1 expression drives immune evasion in BRAFi-resistant melanoma. Cancer Immunology Research, 6(3), 255–266.
Kornepati, A. V. R., Vadlamudi, R. K., & Curiel, T. J. (2022). Programmed death ligand 1 signals in cancer cells. Nature Reviews Cancer, 22(3), 174–189.
Kulkarni, A., Chang, M. T., Vissers, J. H. A., Dey, A., & Harvey, K. F. (2020). The Hippo pathway as a driver of select human cancers. Trends in Cancer, 6(9), 781–796.
Lastwika, K. J., Wilson III, W., Li, Q. K., Norris, J., Xu, H., Ghazarian, S. R., Kitagawa, H., Kawabata, S., Taube, J. M., & Yao, S. (2016). Control of PD-L1 expression by oncogenic activation of the AKT–mTOR pathway in non–small cell lung cancer. Cancer Research, 76(2), 227–238.
Li, S., Ji, J., Zhang, Z., Peng, Q., Hao, L., Guo, Y., Zhou, W., Cui, Q., & Shi, X. (2020). Cisplatin promotes the expression level of PD-L1 in the microenvironment of hepatocellular carcinoma through YAP1. Molecular and Cellular Biochemistry, 475(1), 79–91.
Lin, Y.-T., Ding, J.-Y., Li, M.-Y., Yeh, T.-S., Wang, T.-W., & Yu, J.-Y. (2012). YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway. Experimental Cell Research, 318(15), 1877–1888.
Liu, C., Song, Y., Li, D., & Wang, B. (2023). Regulation of the tumor immune microenvironment by the Hippo Pathway: Implications for cancer immunotherapy. International Immunopharmacology, 122, 110586.
Liu, J., Xiao, Q., Xiao, J., Niu, C., Li, Y., Zhang, X., Zhou, Z., Shu, G., & Yin, G. (2022). Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduction and Targeted Therapy, 7(1), 3.
Liu, M., Yan, M., Lv, H., Wang, B., Lv, X., Zhang, H., Xiang, S., Du, J., Liu, T., & Tian, Y. (2020). Macrophage K63-linked ubiquitination of YAP promotes its nuclear localization and exacerbates atherosclerosis. Cell Reports, 32(5).
Liu-Chittenden, Y., Huang, B., Shim, J. S., Chen, Q., Lee, S.-J., Anders, R. A., Liu, J. O., & Pan, D. (2012). Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes & Development, 26(12), 1300–1305.
Lüönd, F., Pirkl, M., Hisano, M., Prestigiacomo, V., Kalathur, R. K. R., Beerenwinkel, N., & Christofori, G. (2022). Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching. Life Science Alliance, 5(2).
Lv, X., Liu, J., Ruan, J., Chen, P., He, C., Zhao, X., Huang, C., Chen, L., Wang, H., & Hua, G. (2025). Targeting the disrupted Hippo signaling to prevent neoplastic renal epithelial cell immune evasion. Nature Communications, 16(1), 2858.
Massagué, J. (2008). TGFβ in cancer. Cell, 134(2), 215–230.
Mo, J., Park, H. W., & Guan, K. (2014). The Hippo signaling pathway in stem cell biology and cancer. The EMBO Reports, 15(6), 642–656.
Moroishi, T., Hansen, C. G., & Guan, K.-L. (2015). The emerging roles of YAP and TAZ in cancer. Nature Reviews Cancer, 15(2), 73–79.
Moroishi, T., Hayashi, T., Pan, W.-W., Fujita, Y., Holt, M. V, Qin, J., Carson, D. A., & Guan, K.-L. (2016). The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell, 167(6), 1525–1539.
Peng, L., Zhou, L., Li, H., Zhang, X., Li, S., Wang, K., Yang, M., Ma, X., Zhang, D., & Xiang, S. (2024). Hippo-signaling-controlled MHC class I antigen processing and presentation pathway potentiates antitumor immunity. Cell Reports, 43(4).
Qin, K., Yu, M., Fan, J., Wang, H., Zhao, P., Zhao, G., Zeng, W., Chen, C., Wang, Y., & Wang, A. (2024). Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes & Diseases, 11(1), 103–134.
Slemmons, K. K., Crose, L. E. S., Riedel, S., Sushnitha, M., Belyea, B., & Linardic, C. M. (2017). A novel notch–YAP circuit drives stemness and tumorigenesis in embryonal rhabdomyosarcoma. Molecular Cancer Research, 15(12), 1777–1791.
Sun, J.-G., Chen, X.-W., Zhang, L.-P., Wang, J., & Diehn, M. (2015). Yap1 promotes the survival and self-renewal of breast tumor initiating cells via inhibiting Smad3 signaling. Oncotarget, 7(9), 9692.
Sunshine, J., & Taube, J. M. (2015). Pd-1/pd-l1 inhibitors. Current Opinion in Pharmacology, 23, 32–38.
Wang, L., Liu, X., Han, Y., Tsai, H., Dan, Z., Yang, P., Xu, Z., Shu, F., He, C., & Eriksson, J. E. (2024). TRAF6 enhances PD-L1 expression through YAP1-TFCP2 signaling in melanoma. Cancer Letters, 590, 216861.
Wang, Z., Wang, F., Ding, X.-Y., Li, T.-E., Wang, H.-Y., Gao, Y.-H., Wang, W.-J., Liu, Y.-F., Chen, X.-S., & Shen, K.-W. (2022). Hippo/YAP signaling choreographs the tumor immune microenvironment to promote triple negative breast cancer progression via TAZ/IL-34 axis. Cancer Letters, 527, 174–190.
White, S. M., Murakami, S., & Yi, C. (2019). The complex entanglement of Hippo-Yap/Taz signaling in tumor immunity. Oncogene, 38(16), 2899–2909.
Yamazaki, T., Akiba, H., Iwai, H., Matsuda, H., Aoki, M., Tanno, Y., Shin, T., Tsuchiya, H., Pardoll, D. M., & Okumura, K. (2002). Expression of programmed death 1 ligands by murine T cells and APC. The Journal of Immunology, 169(10), 5538–5545.
Yu, F., Yu, C., Li, F., Zuo, Y., Wang, Y., Yao, L., Wu, C., Wang, C., & Ye, L. (2021). Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduction and Targeted Therapy, 6(1), 307.
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015). Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell, 163(4), 811–828.
Yu, M., Peng, Z., Qin, M., Liu, Y., Wang, J., Zhang, C., Lin, J., Dong, T., Wang, L., & Li, S. (2021). Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Molecular Cell, 81(6), 1216–1230.
Zerdes, I., Matikas, A., Bergh, J., Rassidakis, G. Z., & Foukakis, T. (2018). Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene, 37(34), 4639–4661.
Zhang, N., Zeng, Y., Du, W., Zhu, J., Shen, D., Liu, Z., & Huang, J.-A. (2016). The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. International Journal of Oncology, 49(4), 1360–1368.
Zhao, B., Wei, X., Li, W., Udan, R. S., Yang, Q., Kim, J., Xie, J., Ikenoue, T., Yu, J., & Li, L. (2007). Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Development, 21(21), 2747–2761.

Details

Primary Language

English

Subjects

Cancer Cell Biology

Journal Section

Review

Authors

Merve Aykaç ^*
0000-0003-0212-3760
Türkiye

Publication Date

June 14, 2026

Submission Date

April 6, 2026

Acceptance Date

May 23, 2026

Published in Issue

Year 2026 Volume: 2 Number: 2

IZ

https://izlik.org/JA34WX83AU

Cite

RIS / Bibtex

APA

Aykaç, M. (2026). An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer. Anatolian Journal of Medical Sciences, 2(2), 11-17. https://izlik.org/JA34WX83AU

AMA

1.Aykaç M. An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer. Anatolian Journal of Medical Sciences. 2026;2(2):11-17. https://izlik.org/JA34WX83AU

Chicago

Aykaç, Merve. 2026. “An Overview of the Relationship Between the PD-1 PD-L1 Axis and the Hippo–YAP TAZ Signaling Pathway in Cancer”. Anatolian Journal of Medical Sciences 2 (2): 11-17. https://izlik.org/JA34WX83AU.

EndNote

Aykaç M (June 1, 2026) An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer. Anatolian Journal of Medical Sciences 2 2 11–17.

IEEE

[1]M. Aykaç, “An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer”, Anatolian Journal of Medical Sciences, vol. 2, no. 2, pp. 11–17, June 2026, [Online]. Available: https://izlik.org/JA34WX83AU

ISNAD

Aykaç, Merve. “An Overview of the Relationship Between the PD-1 PD-L1 Axis and the Hippo–YAP TAZ Signaling Pathway in Cancer”. Anatolian Journal of Medical Sciences 2/2 (June 1, 2026): 11-17. https://izlik.org/JA34WX83AU.

JAMA

1.Aykaç M. An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer. Anatolian Journal of Medical Sciences. 2026;2:11–17.

MLA

Aykaç, Merve. “An Overview of the Relationship Between the PD-1 PD-L1 Axis and the Hippo–YAP TAZ Signaling Pathway in Cancer”. Anatolian Journal of Medical Sciences, vol. 2, no. 2, June 2026, pp. 11-17, https://izlik.org/JA34WX83AU.

Vancouver

1.Merve Aykaç. An Overview of the Relationship Between the PD-1/PD-L1 Axis and the Hippo–YAP/TAZ Signaling Pathway in Cancer. Anatolian Journal of Medical Sciences [Internet]. 2026 Jun. 1;2(2):11-7. Available from: https://izlik.org/JA34WX83AU