YAP/TEAD4/SP1-induced VISTA expression as a tumor cell-intrinsic mechanism of immunosuppression in colorectal cancer

Sep 24, 2026

Hyperactivation of the YAP/TEAD transcriptional complex promotes an immunosuppressive tumor microenvironment. SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer, and PKCζ phosphorylates SP1 after serum stimulation to enhance TEAD4 binding. The SP1-YAP/TEAD4 complex directly upregulates VISTA in CRC cells, suppressing CD8+ T-cell antitumor function and correlating with poor prognosis. A deglycosylation approach improves anti-VISTA antibody detection in clinical samples.

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CategoryHealthcare

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Introduction

Hippo pathway and YAP/TAZ in cancer immunosuppression

VISTA biology and relevance to cancer therapy

[www.nature.com/cdd](www.nature.com/cdd) ARTICLE OPEN YAP/TEAD4/SP1-induced VISTA expression as a tumor cellintrinsic mechanism of immunosuppression in colorectal cancer Zhehui Zhu1,2,3,4, Rui Ding 1,3,4, Wei Yu 2, Yun Liu 1,3 ✉, Zhaocai Zhou 2 ✉ 1,3 ✉ and Chen-Ying Liu © The Author(s) 2025 | | | | | --- | --- | --- | | | Hyperactivation of the YAP/TEAD transcriptional complex in cancers facilitates the development of an immunosuppressive tumor microenvironment. Herein, we observed that the transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer (CRC) . In response to serum stimulation, PKCζ (protein kinase C ζ) was found to phosphorylate SP1 and enhance its interaction with TEAD4 . As a result, SP1 enhanced the transcriptional activity of YAP/ TEAD and coregulated the expression of a group of YAP/TEAD target genes. The immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) was identiﬁed as a direct target of the SP1-YAP/TEAD4 complex and found to be widely expressed in CRC cells. Importantly, YAP-induced VISTA upregulation in human CRC cells was found to strongly suppress the antitumor function of CD8+ T cells. Consistently, elevated VISTA expression was found to be correlated with hyperactivation of the SP1-YAP/TEAD axis and associated with poor prognosis of CRC patients. In addition, we found by serendipity that enzymatic deglycosylation signiﬁcantly improved the anti-VISTA antibody signal intensity, resulting in more accurate detection of VISTA in clinical tumor samples. Overall, our study identiﬁed SP1 as a positive modulator of YAP/TEAD for the transcriptional regulation of VISTA and developed a protein deglycosylation strategy to better detect VISTA expression in clinical samples. These ﬁndings revealed a new | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | tumor cell-intrinsic mechanism of YAP/TAZ-mediated cancer immune evasion. | | | | | Cell Death & Differentiation (2025) 32:911–925; [https://doi.org/10.1038/s41418-025-01446-2](https://doi.org/10.1038/s41418-025-01446-2) | | | | | | INTRODUCTION The Hippo pathway has been identiﬁed as a key signaling pathway that plays a vital role in controlling organ size and tissue homeostasis [1, 2] . Dysregulation of the Hippo pathway has been widely observed in various cancers, including colorectal cancer (CRC) [3–5] . Activation of YAP/TAZ, the main downstream effectors of the Hippo pathway, modulates the transcription of a series of downstream target genes, mainly through cooperation with TEAD transcription factor members (TEAD1-4), and has been linked to tumor growth, survival, metastasis, and drug resistance [3–6] . Recent studies have also revealed the crucial role of YAP/TAZ in facilitating the development of an immunosuppressive tumor microenvironment (TME) [7–9] . YAP-induced expression of tumorderived cytokines enhances the recruitment of tumor-inﬁltrating macrophages, MDSCs and Tregs [10–12] . In addition, YAP/TAZ directly promote the transcription of the PDL1 gene, which encodes programmed cell death 1 ligand 1 expressed on the tumor cell surface, thus inducing activated T-cell apoptosis and driving immune evasion [13–15] . Although the regulatory axis of YAP/TAZ-PDL1 has been shown in breast, lung and melanoma cancer cell lines, the biological relevance of the YAP/TAZ-PDL1 axis may be dependent on the cell context and has not been studied in traditional syngeneic or genetically engineered mouse models [7–9] . V-domain Ig suppressor of T-cell activation (VISTA), which is encoded by the VSIR or C10ORF54 gene, is a B7 family member that maintains T-cell quiescence and mediates the immunoinhibitory function of myeloid-derived suppressor cells (MDSCs); therefore, VISTA is a promising immune checkpoint target for cancer immunotherapy [16–18] . VISTA has been shown to bind w

FAQs

How does SP1 influence YAP/TEAD activity in colorectal cancer?

SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci, and it enhances YAP/TEAD transcriptional activity together with TEAD4.

What role does VISTA play in tumor immune evasion according to the study?

YAP-induced VISTA upregulation in colorectal cancer strongly suppresses the antitumor function of CD8+ T cells, supporting a mechanism of immune evasion.

Why was enzymatic deglycosylation used in clinical sample analysis?

Enzymatic deglycosylation significantly improves the anti-VISTA antibody signal intensity, enabling more accurate detection of VISTA in clinical tumor samples.

Sep 24, 2026

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