一种新型PARP7抑制剂通过免疫激活和肿瘤内在生长抑制表现出双重抗肿瘤活性

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.