A novel oligo-PROTAC strategy was developed to selectively and specifically degrade activated STAT3 in cells, offering a promising approach for cancer therapy. This strategy involves conjugating a STAT3-specific decoy oligodeoxynucleotide (ODN) with thalidomide, a ligand for the cereblon (CRBN) protein in the E3 ubiquitin ligase complex, to form a proteolysis-targeting chimera (STAT3DPROTAC). Computational modeling predicted two lysine residues (K601 and K626) in STAT3 as potential ubiquitination sites, and mutations at these sites or proteasome inhibition reduced the effectiveness of STAT3DPROTAC. To enhance cell-selectivity, the STAT3DPROTAC was conjugated with a CpG oligonucleotide targeting Toll-like receptor 9 (TLR9), resulting in a myeloid/B cell-selective C-STAT3DPROTAC. This conjugate was efficiently internalized by TLR9-positive cells, including myeloid cells, B cells, and lymphoma cells, but not by T cells. C-STAT3DPROTAC significantly reduced STAT3 protein levels and inhibited STAT3-regulated genes critical for lymphoma cell proliferation and survival. In mouse models, local administration of C-STAT3DPROTAC led to tumor regression, while control treatments had limited effects. The study highlights the potential of using PROTAC strategies for cell-selective targeting of undruggable transcription factors like STAT3, offering a new approach for cancer therapy. The results demonstrate the feasibility of using oligo-PROTACs for targeted degradation of STAT3, with potential applications in other tumorigenic transcription factors. The study also addresses challenges in delivering oligonucleotide therapeutics and emphasizes the importance of cell-selectivity in minimizing off-target effects. The approach combines rational design with computational modeling to optimize the interaction between the target protein and the E3 ubiquitin ligase complex, enhancing the potency and specificity of the therapy. The findings suggest that oligo-PROTACs could provide a safe and effective treatment for B cell lymphoma and potentially other cancers.A novel oligo-PROTAC strategy was developed to selectively and specifically degrade activated STAT3 in cells, offering a promising approach for cancer therapy. This strategy involves conjugating a STAT3-specific decoy oligodeoxynucleotide (ODN) with thalidomide, a ligand for the cereblon (CRBN) protein in the E3 ubiquitin ligase complex, to form a proteolysis-targeting chimera (STAT3DPROTAC). Computational modeling predicted two lysine residues (K601 and K626) in STAT3 as potential ubiquitination sites, and mutations at these sites or proteasome inhibition reduced the effectiveness of STAT3DPROTAC. To enhance cell-selectivity, the STAT3DPROTAC was conjugated with a CpG oligonucleotide targeting Toll-like receptor 9 (TLR9), resulting in a myeloid/B cell-selective C-STAT3DPROTAC. This conjugate was efficiently internalized by TLR9-positive cells, including myeloid cells, B cells, and lymphoma cells, but not by T cells. C-STAT3DPROTAC significantly reduced STAT3 protein levels and inhibited STAT3-regulated genes critical for lymphoma cell proliferation and survival. In mouse models, local administration of C-STAT3DPROTAC led to tumor regression, while control treatments had limited effects. The study highlights the potential of using PROTAC strategies for cell-selective targeting of undruggable transcription factors like STAT3, offering a new approach for cancer therapy. The results demonstrate the feasibility of using oligo-PROTACs for targeted degradation of STAT3, with potential applications in other tumorigenic transcription factors. The study also addresses challenges in delivering oligonucleotide therapeutics and emphasizes the importance of cell-selectivity in minimizing off-target effects. The approach combines rational design with computational modeling to optimize the interaction between the target protein and the E3 ubiquitin ligase complex, enhancing the potency and specificity of the therapy. The findings suggest that oligo-PROTACs could provide a safe and effective treatment for B cell lymphoma and potentially other cancers.