Targeting PARP14 to Suppress Tumor-Promoting Macrophages and Induce Inflammatory Responses

PARP14, a member of the monoPARP sub-family, is an interferon-stimulated gene that is overexpressed in tumors and linked to the promotion of pro-tumor macrophage polarization. Its role in regulating IL-4 and IFN-γ signaling pathways suggests a connection to immune suppression in tumors. However, the development of selective PARP14 inhibitors has been challenging.

This study introduces RBN012759, a newly discovered chemical probe that potently inhibits PARP14 with high selectivity. The compound's development was facilitated by insights into the binding pockets of PARP14 and the broader PARP family, supported by X-ray co-crystal structures. RBN012759 is cell permeable, soluble, and effectively stabilizes endogenous PARP14, inhibiting MARylation in primary human macrophages.

The probe reverses the pro-tumor gene expression driven by IL-4 in macrophages, aligning with previous findings from PARP14 knockout studies and further implicating PARP14 in immune suppression within tumors. Additionally, the study shows that inhibiting PARP14 in human tumor explants can trigger an inflammatory mRNA signature akin to that induced by immune checkpoint therapy.

In summary, RBN012759 represents a significant advancement as the first potent and selective PARP14 inhibitor, enabling further investigation into PARP14's role in macrophage polarization and inflammatory pathways. The compound's effects on gene expression in macrophages and its ability to elicit inflammatory responses in tumor explants underscore PARP14's potential as a target for cancer immunotherapy.