Abstract 4864: The dysregulated YY1-EZH2-RKIP axis in cancer and immune evasion

Background: The current treatment strategies for cancer have evolved with novel effective approaches, particularly immunotherapy. These have resulted in significant tumor regression and prolongation of survival in a subset of cancer patients. However, there is a subset that is initially unresponsive and a responsive subset that becomes subsequently unresponsive leading to tumor progressions and deaths. Rationale: To develop a new immune-therapeutic approach to reverse resistance. Hypothesis: We hypothesized that the unresponsive cancers have in common pivotal gene factors that regulate the resistance and, therefore, are amenable for targeting. These gene factors are the over-expressed Yin Yang1 (YY1) and EZH2 tumor promoters and the under-expressed Raf kinase inhibitor protein (RKIP) tumor suppressor. Altogether, they constitute the dysregulated YY1-EZH2-RKIP axis in cancers and immune evasion. Findings: Analyses of the regulation of expressions of these three gene products revealed that they exhibit cross-talk signaling pathways ( eg the Raf/MEK/ERK, NF-kB, PI3K/Akt). YY1 and EZH2 activate pathways involved in immune resistance and evasion (e.g., inhibition of T cell effector functions, upregulation of T-cell inhibitory receptors and ligands on cancer cells, infiltration of MDSCs, etc.). In contrast, RKIP reverses YY1 and EZH2 immune inhibitory signaling pathways and enhances the anti-cancer immune response. Conclusion: The findings revealed that the dysregulated YY1-EZH2 -RKIP axis in cancer is involved in the resistance of cancer to various immuno-therapeutics and induces an immune-suppressive TME and immune evasion. Various approaches are presented targeting each of the three gene products, individually or in combination, to reverse immune resistance and restore the effectiveness of anti-cancer immunotherapy. We suggest that further investigations are necessary to validate the targeting strategies, preclinically and then clinically. However, there remain challenges to develop agents that specifically target the cancer cells in vivo with minimal side effects. Citation Format: Benjamin Bonavida, Talia Festekdjian. The dysregulated YY1-EZH2-RKIP axis in cancer and immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4864.