RECQL4 affects MHC class II-mediated signalling and favours an immune-evasive signature that limits response to immune checkpoint inhibitor therapy in patients with malignant melanoma.

Background: Cancer immunotherapy has transformed metastatic cancer treatment, yet challenges persist regarding therapeutic efficacy. RECQL4, a RecQ-like helicase, plays a central role in DNA replication and repair as part of the DNA damage response, a pathway implicated in enhancing efficacy of immune checkpoint inhibitor (ICI) therapies. However, its role in patient response to ICI remains unclear.

Structure-based discovery of first inhibitors targeting the helicase activity of human PIF1.

PIF1 is a conserved helicase and G4 DNA binding and unwinding enzyme, with roles in genome stability. Human PIF1 (hPIF1) is poorly understood, but its functions can become critical for tumour cell survival during oncogene-driven replication stress. Here we report the discovery, via an X-ray crystallographic fragment screen (XChem), of hPIF1 DNA binding and unwinding inhibitors.

Glucocorticoid activation by HSD11B1 limits T cell-driven interferon signaling and response to PD-1 blockade in melanoma.

Background: Immune responses against tumors are subject to negative feedback regulation. Immune checkpoint inhibitors (ICIs) blocking Programmed cell death protein 1 (PD-1), a receptor expressed on T cells, or its ligand PD-L1 have significantly improved the treatment of cancer, in particular malignant melanoma. Nevertheless, responses and durability are variables, suggesting that additional critical negative feedback mechanisms exist and need to be targeted to improve therapeutic efficacy.