Advances in BCL6-targeted cancer therapy: From functional inhibition to PROTAC degradation

B-cell lymphoma 6 (BCL6) is a transcriptional repressor essential for germinal center B-cell development, differentiation, and immune regulation. Aberrant overexpression or dysfunction of BCL6 drives lymphomagenesis, particularly in diffuse large B-cell lymphoma. Conventional small-molecule inhibitors have limitations such as poor selectivity and incomplete target inhibition. Proteolysis-targeting chimera (PROTAC) technology offers a strategy to overcome these limitations by facilitating the targeted degradation of BCL6. This review systematically outlines the progress of BCL6-targeted therapy from functional inhibition to protein degradation by analyzing preclinical and clinical data. PROTAC-based degraders exhibit better efficacy and specificity than traditional inhibitors, and early clinical trials support the therapeutic potential of BCL6 degradation. Although PROTACs have advanced BCL6-targeted treatment, several challenges remain. This review highlights current obstacles and future directions to guide rational therapeutic design.