PYGO2 Ablation Promotes Lymphoid Organization and STING-Dependent Antitumor Immunity in Prostate Cancer.

Authors

Yini Zhu, Yan Liu, Ziyu Zeng, Qi Huo, Minzhi Liang, Shiyu Wang, Nipuni Barupala, Xuemin Lu, Jun Wan, Liang Cheng, Xin Lu

Published in

Cancer letters. Pages 218862. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Prostate cancer is an immunologically cold tumor with a limited response to immune checkpoint blockade. Although tertiary lymphoid structures (TLSs) are associated with favorable immunotherapeutic outcomes in various malignancies, the tumor-intrinsic mechanisms governing their formation in prostate cancer remain poorly defined. We investigated whether the frequently amplified chromatin effector PYGO2 regulates lymphoid organization and antitumor immunity. Using prostate-specific Pten/Smad4 double-knockout and Pten/Smad4/Pygo2 triple-knockout mice, syngeneic tumors, transcriptomics, single-cell RNA sequencing, and immunostaining, we found that Pygo2 ablation restored androgen receptor signaling, reduced neuroendocrine-associated features, delayed castration-resistant progression, and prolonged survival. Pygo2-deficient tumors expressed higher levels of tertiary lymphoid structure (TLS)-associated chemokines, exhibited greater T- and B-cell infiltration, and developed TLS-like structures. Single-cell profiling showed increased CD8/Treg ratios, B-cell abundance, TLS imprint scores, and antigen-presentation signatures, particularly after combination therapy. Pygo2 loss also increased DNA damage and was accompanied by activation of the STING-interferon axis. In RM1 syngeneic tumors, STING silencing attenuated the Pygo2-loss-associated increase in cytokine expression, immune infiltration, apoptosis, and tumor control. Combining Pygo2 ablation with castration, CXCR1/2 inhibition, and dual PD-1/CTLA-4 blockade produced durable disease control in more than 80% of Pygo2-deficient mice. These findings identify PYGO2 as a tumor-intrinsic regulator of castration resistance and antitumor immunity and support combining PYGO2-directed strategies with androgen deprivation, myeloid suppression, and immune checkpoint blockade in prostate cancer.

PMID:
42810571
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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