What question did this study set out to answer?

This research aims to find ways to selectively inhibit PRMT5 to overcome immune resistance in cancer treatment, particularly for tumors with MTAP loss.

July 4, 2026

Abstract P49: Target PRMTs to Overcome Cancer Immune Resistance

Key Points

This research aims to find ways to selectively inhibit PRMT5 to overcome immune resistance in cancer treatment, particularly for tumors with MTAP loss.
Developed isogeneic tumor lines with and without MTAP loss to test PRMT5 inhibitors.
Evaluated the effects of the inhibitors GSK3326595 and MRTX1719 in vitro and in vivo.
Conducted transcriptomic and proteomic profiling to analyze the mechanism of action.
GSK3326595 significantly reduced PRMT5 activity in both tumors and T cells, independent of MTAP status.
MRTX1719 specifically inhibited PRMT5 in MTAP-loss tumors with minimal effects on immune suppression.
Combining MRTX1719 with immune checkpoint blockade resulted in greater antitumor effects in murine models with MTAP-loss tumors.

Abstract

Abstract Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Genetic screens and other preclinical studies reveal tumor intrinsic PRMTs can suppress T-cell mediated antitumor immune responses, highlighting the possibility of combining PRMT inhibitors (PRMTi) with cancer immunotherapy. However, global suppression of PRMT activity is expected to impair the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP) -loss cancer. We generated a set of isogeneic tumor lines with and without MTAP loss, and evaluated the effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) in these isogenic tumor lines and T cells in vitro and in vivo. We found that GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of MTAP status. However, MRTX1719, a methylthioadenosine (MTA) -cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces activation of the PI3K pathway, a well-documented immune-resistant pathway. Furthermore, the combination of MRTX1719 in combination with immune checkpoint blockade (ICB) leads to superior antitumor activity in two syngeneic murine models with MTAP-loss tumor. Collectively, our results provide a strong rationale for the clinical development of PRMT5i-based IO combinations. Citation Format: Si Chen, Jiakai Hou, Roshni Jaffery, Ashley M. Guerrero, Rongjie Fu, Leilei Shi, Ningbo Zheng, Ritu Bohat, Nicholas A. Egan, Chengtai Yu, Sana Sharif, Yue Lu, Wei He, Shuyue Wang, Donjeta Gjuka, Everett M. Stone, Pooja Anil Shah, Jordi Rodon, Taiping Chen, Xinli Liu, Mark T. Bedford, Han Xu, Weiyi Peng. Target PRMTs to Overcome Cancer Immune Resistance abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr P49.

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