GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329594/suppl/GSE329594_NormalizedCount_gene_TE_analysis.txt.gzftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329594/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329594GEOGSEfalseTargeted Degradation of SETDB1 by an Aptamer-CRBNL PROTAC as a Novel Therapeutic Strategy for Breast CancerPROteolysis TArgeting Chimeras (PROTACs) represent a novel therapeutic strategy that leverages the ubiquitin-proteasome system for targeted protein degradation. Aptamers, with their high specificity and binding affinity, have recently been explored as alternative recognition elements in PROTAC design. Here, we developed an aptamer-based PROTAC targeting SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), an epigenetic regulator implicated in breast cancer progression. The SETDB1-specific aptamer identified in our previous work was conjugated to a CRBN E3 ligase ligand via click chemistry, generating a serum-stable PROTAC, designated as P-SETDB1-4. P-SETDB1-4 effectively recruits CRBN to SETDB1, inducing proteasome-dependent degradation of SETDB1 in breast cancer cells. Consequently, P-SETDB1-4 significantly inhibits the proliferation and migration of breast cancer cells. Moreover, P-SETDB1-4 enhances the CD8+ T cells cytotoxicity against breast cancer cells and suppresses tumor growth in vivo. RNA sequencing analysis elucidates the molecular mechanism underlying P-SETDB1-4-mediated tumor suppression and promotion of CD8+ T cell-mediated killing. This study provides a promising therapeutic strategy for breast cancer and highlights the potential of aptamer-CRBNL PROTACs for targeting other challenging oncogenic proteins.2026/05/05GSE329594GSM9707150GSM9707149GSM9707147GSM970714824676329594Homo sapiens