Abstract Background: The Janus kinase/Signal transducer and activator of transcription (JAK-STAT) pathway is one of the core cancer pathways that integrates signals from cytokines, hormones and growth factors to induce or repress gene expression in cells. The pathway consists of four JAK kinases and seven STAT transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6). STAT3 is the best-studied family member of the JAK-STAT pathway in cancer and is a known oncogene in various types of tumor. Besides its important role in cancer development, STAT3 is also essential in normal tissues. Completely blockage of STAT3 can lead to serious side effects. How to balance the efficacy and adverse effect is a critical issue in development of STAT3 inhibitor. HZ-R078 is a novel selective STAT3 degrader which exhibits long-lasting STAT3 degradation effect in tumor tissue, while the clearance in plasma and other organs are high. Based on this unique PK character, HZ-R078 shows potent efficacy and high safety. Experimental Design: In-vitro STAT3 degradation was evaluated in various caner cell lines. In-vitro wash-out assay was conducted in a one-week cycle. In this wash-out assay, SU-DHL1 cells in different groups were treated with HZ-R078 at the concentration of DC95 for 24, 48, 72h firstly, then the drug was washed out, the cell growth and STAT3 protein level were evaluated daily in next 6, 5, 4 days recovery-period respectively. PK/PD study was performed in SU-DHL1 xenograft model in a 168 h-period. The drug concentration was determined in plasma and tumor tissue at different time points, the STAT3 degradation rate was also evaluated in corresponding tumor tissues. In-vivo anti-tumor effect was determined in two T-cell lymphoma models. Results: HZ-R078 can completely degrade STAT3 in various types of cell, the DC50 values ranges from 5 to 150 nano-molar. In wash-out assay, we demonstrated that maintain the drug concentration above DC95 for more than 48 hours can completely suppress the STAT3 level and irreversibly inhibit the cell growth in the following recovery-period in T-cell lymphoma cell lines. This important finding was further validated in PK/PD study. In PK/PD study, we also find that HZ-R078 has much lower clearance in tumor tissue than plasma and other organs. The ratio of plasma AUC to tumor AUC is approximate to 1. In in-vivo anti-tumor evaluation, HZ-R078 can significantly suppress the growth of tumor in SU-DHL1 and Karpass299 models in a weekly administration. In pre-clinical safety study, HZ-R078 exhibits higher MTD dose in Rats. Conclusion: HZ-R078 is a selective and potent STAT3 degrader which has tumor-enriched distribution character. The pre-clinical efficacy and safety study support its further development in clinical stage for T-cell lymphoma therapy. Citation Format: Yizhe Wu, Xinxin Jin, Xinglu Zhou. HZ-R078: A tumor-enriched STAT3 degrader for treating T-cell lymphoma in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3109.