Targeting the master of the replication fork-PCNA.

Proliferating cell nuclear antigen (PCNA) orchestrates DNA replication, repair, stress responses, and cell-cycle control. Because tumors are hyperproliferative and genomically unstable, they are highly dependent on PCNA, creating a therapeutic vulnerability. Strategies under evaluation include direct inhibition of PCNA, disruption of PCNA-partner interactions that govern DNA metabolism and cell-cycle progression, and combination regimens with DNA-damaging agents to enhance chemo- and radiosensitivity. Several agents-most notably the APIM peptide ATX-101 and the allosteric small molecule AOH1996-have progressed beyond preclinical testing and are being evaluated as monotherapies or in combination with radiotherapy and genotoxic chemotherapies in early clinical studies. This review synthesizes the mechanistic rationale, therapeutic modalities, and development landscape of PCNA-targeted interventions, highlighting their potential to improve anticancer efficacy while mitigating toxicity.