The study presents a novel strategy for cell-selective and targeted degradation of activated STAT3 using a decoy oligonucleotide (ODN) conjugated to thalidomide, a ligand for the E3 ubiquitin ligase complex. This approach, termed STAT3DPROTAC, effectively downregulated STAT3 in target cells without affecting other transcription factors like STAT1 or STAT5. Computational modeling predicted two surface lysines (K601 and K626) in STAT3 as potential ubiquitination sites, which were confirmed by point mutations and proteasome inhibition experiments. The STAT3DPROTAC was further conjugated to a CpG ODN targeting Toll-like receptor 9 (TLR9) to create a myeloid/B cell-selective form, C-STAT3DPROTAC, which efficiently reduced STAT3 levels and targeted genes critical for lymphoma cell proliferation and survival. In vivo studies in human Ly3 lymphoma-bearing mice showed that C-STAT3DPROTAC triggered tumor regression, while control treatments had limited effects. The results highlight the potential of using PROTAC strategies for cell-selective targeting of undruggable transcription factors like STAT3 in cancer therapy.The study presents a novel strategy for cell-selective and targeted degradation of activated STAT3 using a decoy oligonucleotide (ODN) conjugated to thalidomide, a ligand for the E3 ubiquitin ligase complex. This approach, termed STAT3DPROTAC, effectively downregulated STAT3 in target cells without affecting other transcription factors like STAT1 or STAT5. Computational modeling predicted two surface lysines (K601 and K626) in STAT3 as potential ubiquitination sites, which were confirmed by point mutations and proteasome inhibition experiments. The STAT3DPROTAC was further conjugated to a CpG ODN targeting Toll-like receptor 9 (TLR9) to create a myeloid/B cell-selective form, C-STAT3DPROTAC, which efficiently reduced STAT3 levels and targeted genes critical for lymphoma cell proliferation and survival. In vivo studies in human Ly3 lymphoma-bearing mice showed that C-STAT3DPROTAC triggered tumor regression, while control treatments had limited effects. The results highlight the potential of using PROTAC strategies for cell-selective targeting of undruggable transcription factors like STAT3 in cancer therapy.