Nucleophagy as an emerging therapeutic vulnerability in cancer

Poly(ADP-ribose) polymerase inhibitors (PARPi) exploit synthetic lethality in homologous recombination-deficient (HRD) cancers by trapping PARP1 on DNA, causing replication fork collapse, DNA double-strand breaks, and ultimately cell death. However, primary and acquired resistance to PARPi remains a major clinical challenge. Here, we describe a previously unrecognized mechanism for the resolution of cytotoxic trapped PARP1 through TEX264-mediated nucleophagy. We identify the p97-TEX264-nucleophagy axis as a critical pathway for the clearance of trapped PARP1 and a promising therapeutic target for overcoming PARPi resistance in HRD cancers.