Abstract 4567: A novel PARP7 inhibitor exhibits dual antitumor activity through immune activation and tumor-intrinsic growth inhibition

Abstract PARP7 (TIPARP, TCDD-induced poly[ADP-ribose] polymerase) is a stress-inducible mono-ADP-ribosyltransferase frequently overexpressed across multiple cancer types. Elevated PARP7 expression has been implicated in tumor progression, immune evasion, and the establishment of an immunosuppressive tumor microenvironment (TME). Mechanistically, in cancer cells, PARP7 negatively regulates type I interferon (IFN) signaling by mono-ADP-ribosylating TBK1, thereby suppressing nucleic acid sensing and dampening antitumor immune activation within the TME. Pharmacological inhibition of PARP7 restores IFN signaling and potentiates immune-mediated antitumor responses. In addition to immune activation, PARP7 inhibition exerts tumor-intrinsic antitumor effects through multiple cellular mechanisms, culminating in direct tumor cell growth inhibition. Collectively, these findings suggest that targeting PARP7 may offer superior therapeutic potential compared with current immuno-oncology (IO) approaches by coupling immune activation with tumor-intrinsic control. In this study, we identified a novel small-molecule PARP7 inhibitor, referred to as compound 1, which exerts dual anticancer mechanisms. Compound 1 demonstrated potent inhibition of PARP7 enzymatic activity in biochemical assays and markedly reduced global mono-ADP-ribosylation (MARylation) in PARP7-inducible SK-MES-1 cells, thereby confirming its activity at the cellular level. From an IO perspective, compound 1 robustly induced interferon-stimulated gene (ISG) expression in RAW-Lucia ISG cells and various cancer cell lines. It also enhanced the activation of multiple immune cell subsets, showing pronounced effects particularly under TME-mimicking conditions. Compound 1 exhibited strong monotherapy activity in syngeneic tumor models and achieved complete responses (CR) when combined with anti-PD-1 or standard chemotherapies. Beyond immune modulation, PARP7 inhibition also mediates tumor-intrinsic growth inhibition. We identified a chromatin-associated trapping mechanism as a primary driver of these intrinsic effects. Correspondingly, compound 1 produced potent growth inhibition across multiple cancer cell lines, including NCI-H1373, and significantly suppressed tumor growth in xenograft models. Notably, across both mechanisms, compound 1 demonstrated comparable or superior activity to RBN2397, a PARP7 inhibitor under clinical evaluation. In summary, our findings highlight PARP7 inhibition as a promising therapeutic strategy that integrates immune activation with tumor-intrinsic growth inhibition. The novel PARP7 inhibitor, compound 1, consistently demonstrated this dual mechanism across diverse preclinical models, supporting its potential as a next-generation therapeutic candidate with both immune-mediated and tumor-intrinsic antitumor activity. Citation Format: Dajeong Kim, Iksoo Jang, Daehyeon Seong, Jeongyoon Shin, Kyu Hwan Kim, SeungHyun Song, Joon Yonug Hwang, Hong Sik Han, Kyung Seok Lee, Boram Lee, Soo-Jung Choi, Song-Yi Lee, Dae Young Lee, Jinhoon Jeong, Hojeong Hong, Haneol Kim, Jongho Cho, Ki Moon Ryu, Mi-Kyung Kim. A novel PARP7 inhibitor exhibits dual antitumor activity through immune activation and tumor-intrinsic growth inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4567.