CCAAT/enhancer-binding protein beta (C/EBPβ) is a master regulator of hepatic metabolism, inflammation, and fibrosis, making it an attractive but underexploited target for metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we demonstrate that GalNAc-conjugated small interfering RNA (siRNA) targeting C/EBPβ (GalNAc-siCEBPβ) significantly improves liver function and metabolic parameters in a high fat diet (HFD) murine model. In vitro, GalNAc-siCEBPβ achieved dose-dependent C/EBPβ mRNA silencing (∼80% knockdown at 0.1 μM) in primary mouse hepatocytes. In vivo, subcutaneous administration (10 mg/kg) reduced hepatic C/EBPβ expression by 45% (p < 0.01), concomitant with a marked reduction in liver steatosis and improved metabolic profile (15% less weight gain, 20% lower glucose, 25% reduced triglycerides), and restored liver function (18% higher albumin, 22% lower bilirubin)—all without hepatotoxicity (ALT/AST unchanged). Notably, these effects occurred despite continued HFD feeding, suggesting disease-modifying potential. By leveraging the precision of RNAi and hepatocyte-specific GalNAc delivery, GalNAc-siCEBPβ addresses key limitations of current MASLD therapies by targeting both metabolism and fibrosis. Our findings support clinical translation for MASLD and its complications, including hepatocellular carcinoma.

Abstract Telomerase (TERT) is an enzyme commonly activated in human cancers and critical for maintaining cell survival. TERT expression and activation correlates with more aggressive, treatment-resistant disease, with the highest telomerase activity in relapsed acute myeloid leukemia (AML) patients. Telomerase inhibitors showed promise in preclinical studies on AML leading to leukemic stem cells (LSC) eradication. However, TERT inhibition in cancer cells faced challenges, such as the delayed clinical responses and on-target/off-tumor toxicities to hematopoietic stem cells (HSCs) or to activated T cells that result in cytopenias or immunosuppression, respectively. We previously developed clinically-relevant strategy for targeted delivery of therapeutic molecules into TLR9+ positive myeloid cells, such as AML cells including LSCs, using synthetic CpG oligodeoxynucleotides (CpG-ODNs) as a targeting domain. Here, we report generation of new CpG-conjugates for the delivery of a synthetic TERT substrate, 6-thio-2’-deoxy-guanosine (6tdG) into AML cells. CpG-6tdG oligonucleotides (CpG-6tdGOs) comprise multiple (5-10) 6tdG nucleosides in the 3’ end of CpG-ODN. The CpG-6tdGOs retain serum stability, while allowing for slow release of the 6tdG nucleotides after uptake into target leukemic cells. In vitro, CpG-6tdG-oligonucleotides (CpG-6tdGOs) were selectively cytotoxic to human TLR9+/TERT+ AML cells without affecting activated TLR9—/TERT+ T-cells, HSCs or non-malignant TERT— cells. The liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis confirmed that 6tdG was effectively incorporated into chromatin of target cancer cells after in vitro and in vivo treatment using CpG-6tdGO. Repeated intravenous injections of CpG-6tdGO, but not 6tdG nucleoside, within days induced cytotoxic effects against xenotransplanted models of primary human AML with diverse genomic background in immunodeficient NSG mice and inhibited leukemia progression. CpG-6tdGO showed enhanced antitumor activity when tested in vivo against syngeneic Cbfb/MYH11/Mpl (CMM) and C1498 mouse AML models. In immunocompetent mice, treatment with CpG-6tdGO induced systemic, cancer cell-selective and CD8 T-cell-mediated antitumor immune responses that were at least partly dependent on TLR9- and STING-mediated signaling in response to CpG-6tdGO-induced cancer cell death. Importantly, the repeated treatments were well-tolerated in humanized hCD34/NOG mice. Except for the reduced percentage of human B-cells, CpG-6tdGO did not decrease the numbers of HSCs, myeloid cells, or T-cells. Overall, CpG-6tdGO offers an effective and safer strategy against aggressive TERT+ hematologic malignancies and potentially certain solid tumors. Citation Format: Chunsong Yu, Elaine Y. Kang, Piotr Swiderski, Haiqing Li, Ya-Huei Kuo, Guido Marcucci, Marcin Kortylewski. Bi-functional thiopurine-based oligonucleotides for AML cell-targeted telomere damage and immunostimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5752.

BACKGROUND:Endothelial cell (EC) dysfunction is both a cause and consequence of vascular inflammation and lipid dysregulation in atherosclerosis, yet the molecular drivers linking EC dysfunction to systemic metabolic derangements remain incompletely understood. We previously identified Argonaute 1 (AGO1)-a canonical component of the RNA-induced silencing complex-as a regulator of EC function in angiogenesis and metabolism. In this study, we uncover a previously unrecognized, non-canonical role of nuclear AGO1 in ECs as a transcriptional coactivator of NF-κB, and demonstrate that EC-specific AGO1 inhibition simultaneously improves lipid metabolism, liver function, and vascular inflammation, thereby attenuating atherosclerosis. METHODS:EC-conditional AGO1 knockout (EC-AGO1-KO) and wildtype mice were subjected to pro-atherosclerotic models induced by AAV9-PCSK9 and a western diet, or carotid artery ligation. Metabolic and vascular phenotyping and gene expression analyses were performed. In human liver sinusoidal ECs (HLSECs) and human aortic ECs (HAECs), AGO1 was knocked down using antisense oligos (ASO), followed by assays for inflammatory responses (qPCR, RNA-seq, ELISA, and monocyte adhesion). Mechanistic studies included Cut&Tag sequencing, and chromatin immunoprecipitation assays, and EC-hepatocyte co-cultures. Therapeutic effect of AGO1 inhibition was assessed using lipid nanoparticle (LNP)-delivered ASO in mice. RESULTS:EC-AGO1-KO mice exhibited significantly improved plasma lipid profiles, reduced hepatic steatosis, inflammation, and fibrosis, and decreased aortic atherosclerotic burden. AGO1 knockdown in ECs dampened inflammatory responses and monocyte recruitment and enhanced hepatocyte lipid metabolism via paracrine signaling. Mechanistically, nuclear AGO1 interacted with NF-κB p65 to enhance transcription of pro-inflammatory genes including ICAM1 , THBS1 . LNP-delivered AGO1-ASO improved hyperlipidemia, liver function, and atherosclerosis without evident hepatotoxicity. CONCLUSIONS:Endothelial AGO1 promotes vascular inflammation and liver dysfunction through a non-canonical role as an NF-κB coactivator. Its inhibition provides dual benefits-ameliorating lipid dysregulation and suppressing vascular inflammation-highlighting EC-AGO1 as a promising therapeutic target for atherosclerosis and cardiometabolic diseases.

BACKGROUND:Therapeutic resistance in glioblastoma (GBM) is multifactorial and results from genetic heterogeneity, the immunoprivileged localization, and the potently tolerogenic microenvironment. Signal transducer and activator of transcription 3 (STAT3) plays a key role in both glioma cell survival and immune evasion, reinforcing GBM resistance. METHODS:Here, we describe a new cell-selective and double-stranded STAT3 antisense oligonucleotide (CpG-STAT3dsASO) for targeting human/mouse glioma cells and GAMs but not T cells. The oligonucleotide safety and efficacy against orthotopic GBM was assessed in immunocompetent or immunodeficient mice. RESULTS:CpG-STAT3dsASO injected intracranially/intratumorally was well-tolerated and reduced progression of human U251 GBM xenotransplants and mouse GL261 or neural cell-derived QPP8 gliomas. Unlike the single-stranded oligonucleotide, local CpG-STAT3dsASO administration did not trigger type-I IFN-dependent neurotoxicities in immunocompetent mice within the therapeutic dose range. CpG-STAT3dsASO activated intratumoral GAMs, such as dendritic cells, macrophages and microglia, thereby expanding CD4+ Th1 cells while reducing TREG numbers. CpG-STAT3dsASO monotherapy did not have curative effects as it led to recruitment of only limited numbers of mostly exhausted effector CD8+ T cells. However, when combined with systemic PD1 inhibition, CpG-STAT3dsASO/anti-PD1 treatments caused regression of GL261 as well as immunotherapy-resistant QPP8 gliomas and resulted in long-term survival of the majority of mice. The combination treatment boosted CD8+ effector T-cell activity, while promoting their intratumoral interaction with activated CD4+ Th1 cells and activated macrophages as indicated by spatial transcriptomics. CONCLUSIONS:Our results suggest rationale for GBM immunotherapy using CpG-STAT3dsASO to disrupt GAMs-dependent immune evasion, thereby restoring sensitivity to PD1 blockade and facilitating T-cell-mediated antitumor immune responses.

We previously demonstrated that blocking tolerogenic signal transducer and activator of transcription 3 (STAT3) signaling in the tumor microenvironment can unleash Toll-like receptor 9 (TLR9)-mediated antitumor immunity. To enable systemic administration of minimally modified CpG-siSTAT3, we developed a panel of MC3-based lipid nanoparticle (LNP) formulations optimized for targeting immune cells and B cell lymphoma cells. The selected LNP2(CpG-siSTAT3) induced potent type I interferon (IFN) production in human peripheral blood mononuclear cells (PBMCs) and resulted in >50% STAT3 knockdown in human cancer cells at low oligonucleotide concentrations. In vivo, LNP2(CpG-siSTAT3) showed a 10-fold improvement in potency against B cell lymphoma xenotransplants compared to the naked oligonucleotide. Further changes in chemical composition yielded LNP2.1, which preferentially targeted human monocytes and dendritic cells (DCs). In A20 lymphoma-bearing mice, the fluorescently labeled LNP2.1(CpG-siSTAT3) quickly drained to local tumor-draining lymph nodes (TDLNs) after subcutaneous injection and was taken up by activated DCs and macrophages. Furthermore, LNP2.1(CpG-siSTAT3) administration significantly reduced A20 tumor growth by rapidly activating DCs and macrophages in TDLNs, thereby promoting T cell activation and specifically increasing tumor-infiltrating cytotoxic CD8 T cells secreting IFNγ and tumor necrosis factor alpha. The LNP2.1 formulation offers an effective vehicle for targeting tolerogenic myeloid cells in the B cell lymphoma microenvironment and potentially in solid tumors.

Telomerase (TERT) is an enzyme involved in maintaining telomere length in diffuse large B cell lymphoma (DLBCL). Previous attempts to target TERT+ cancers faced challenges, including the delayed clinical responses and on-target/off-tumor toxicities. Here, we present a DLBCL-targeted oligonucleotide designed to deliver a synthetic TERT substrate, 6-thio-2'-deoxy-guanosine (6tdG), damaging telomeres and triggering apoptosis. In vitro, 6tdG-oligonucleotides (6tdGOs) were selectively cytotoxic to TERT+ DLBCL cells without affecting activated T cells or non-malignant TERT- cells. Repeated intravenous administration of 6tdGO, but not 6tdG nucleoside, had significant antitumor effects against xenotransplanted human DLBCL models and syngeneic Eμ-myc/15A lymphoma in mice. In immunocompetent mice, treatment with 6tdGO induced systemic, lymphoma-specific, and CD8 T cell-mediated antitumor immune responses. The abscopal effects of 6tdGO were abolished in mice lacking expression of Sting1 or Ifnar1 but not Trl9. These findings suggest that 6tdGO-induced lymphoma cell death triggered STING-mediated type-I interferon signaling, thereby promoting recruitment/activation of CD8 T cells. Importantly, the repeated 6tdGO treatments were well-tolerated in humanized hCD34/NOG mice. Except for the reduced percentage of human B cells, 6tdGO did not decrease the numbers of hematopoietic stem cells, myeloid cells, or T cells. Overall, 6tdGO offers an effective and safer strategy against aggressive TERT+ DLBCL with potential to activate T cell-based antitumor immunity.

Delivery across the blood–brain barrier (BBB) is one of the most challenging tasks for modern biopharmaceutics. Many attempts have been taken, with only low delivery efficacies achieved so far. We report a new transferrin receptor-targeting (TfR) RNA aptamer conjugated to DSPE lipid that leads to an unprecedented effective uptake in the brain, with brain-to-serum ratios up to 6.5 in mice. This result is superior to recently published values of < 1 for antibody conjugates and nanovesicles, pointing to a successful combined effect of the increased lipophilicity and TfR targeting with the new RNA aptamer that our conjugate provides. Using fluorescence whole body imaging, polymerase-chain reaction (PCR) and fluorescence in situ hybridization, we confirm that the new conjugate delivers high amounts of DNA oligonucleotide to brains of Balb/cJ mice, and it is effective in human cells. There is no acute toxicity as verified with histopathological assessment of mice organs. The combination of properties demonstrated by our new conjugate makes it a highly potent delivery tool that can be applied in therapy of brain diseases incl. glioblastoma, neurogenerative diseases, and a broad range of brain infections.

Triple-negative breast cancer (TNBC) is a form of breast cancer clarified by low expression of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2). For this reason, therapeutics aimed at targeting these receptors are ineffective in cases of TNBC, which leads to a poorer prognosis. Consequently, there is a need for novel therapeutics at targeting this subtype. CCAAT/enhancer-binding protein β (C/EBPβ) is a leucine zipper transcription factor with a traditional function in mammary gland development and macrophage differentiation. In tumors, C/EBPβ is associated with metastatic and chemoresistant forms of breast cancer. Previous efforts at targeting this transcription factor in the tumor have been hampered by off-target effects and low penetrance into the intratumoral space. Furthermore, studies into C/EBPβ knockdown in vitro have been mixed, owing in part to two distinct isoforms that are differentially expressed in healthy and cancerous tissues. Given that the function of C/EBPβ is closely tied to hypoxia factors such as hypoxia-inducible factor-1α, we hypothesized that the hypoxic intratumoral space may be driving specific isoform development and consequently the pro-metastatic phenotype observed clinically. To this end, we have developed an aptamer-small interfering RNA (siRNA) conjugate containing a transferrin receptor 1 (TfR1) aptamer (a receptor activated under hypoxic conditions) linked to a C/EBPβ siRNA. We have measured C/EBPβ's suppression of metastasis in traditional cell culture under hypoxic conditions and in vivo. These results point toward a novel approach to the contradictory role of C/EBPβ as a driver and mediator of metastasis and a potential therapeutic for its treatment.

We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells' metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.

Immune checkpoint blockade (ICB) therapy has significantly benefited patients with several types of solid tumors and some lymphomas. However, many of the treated patients do not have a durable clinical response. It has been demonstrated that rescuing exhausted CD8+ T cells is required for ICB-mediated antitumor effects. We recently developed an immunostimulatory strategy based on silencing STAT3 while stimulating immune responses by CpG, a ligand for Toll-like receptor 9 (TLR9). The CpG-small interfering RNA (siRNA) conjugates efficiently enter immune cells, silencing STAT3 and activating innate immunity to enhance T cell-mediated antitumor immune responses. In the present study, we demonstrate that blocking STAT3 through locally delivered CpG-Stat3 siRNA enhances the efficacies of the systemic PD-1 and CTLA4 blockade against mouse A20 B cell lymphoma. In addition, locally delivered CpG-Stat3 siRNA combined with systemic administration of PD-1 antibody significantly augmented both local and systemic antitumor effects against mouse B16 melanoma tumors, with enhanced tumor-associated T cell activation. Furthermore, locally delivered CpG-Stat3 siRNA enhanced CD8+ T cell tumor infiltration and antitumor activity in a xenograft tumor model. Overall, our studies in both B cell lymphoma and melanoma mouse models demonstrate the potential of combinatory immunotherapy with CpG-Stat3 siRNA and checkpoint inhibitors as a therapeutic strategy for B cell lymphoma and melanoma.

Abstract Telomerase (TERT) is an enzyme critical for carcinogenesis expressed in about 90% of human cancers, including aggressive diffuse large B-cell lymphoma (DLBCL). Targeting TERT proven difficult due to on-target toxicities to non-malignant hematopoietic stem cells and potentially to activated immune effector cells. To overcome these challenges, we developed novel TLR9+ cell-selective CpG-oligodeoxynucleotides (ODNs) to deliver telomere-damaging nucleoside analogue, 6-thio-2’-deoxy-guanosine (6tdG), into target B cell lymphoma cells in vitro and in vivo. Human and mouse TLR9+/TERT+ lymphoma cells rapidly internalized CpG(6tdG)-oligonucleotides through active endocytosis. 6tdG molecules were released from the 3’ end of the oligonucleotide into cytosol and cell nucleus. TERT-mediated 6tdG incorporation into telomeres, led to DNA damage and lymphoma cell death. In vitro, CpG(6tdG)-oligonucleotides showed potency in targeting variety of human DLBCL cells in nanomolar range without detectable toxicity to non-malignant TERT— cells or human TERT+ hematopoietic stem cells and activated T cells. Importantly, the repeated systemic administration of CpG(6tdG)-oligonucleotides was well-tolerated by humanized hCD34/NOG mice, without detectable decrease in the percentage of hematopoietic stem cells, myeloid cells or T cells although the numbers of B cells were partly reduced as expected. Intravenously injected CpG(6tdG)-oligonucleotides, but not 6tdG nucleoside, had potent and dose-dependent antitumor effects against xenotransplanted models of human GC- or ABC-subtypes of DLBCL, such as OCI-Ly18 or OCI-Ly3, respectively. Furthermore, we assessed CpG(6tdG)-oligonucleotide activity against aggressive, syngeneic TERT+ Eμ-myc/15A lymphoma in immunocompetent mice. CpG(6tdG)-oligonucleotide, but not the CpG-oligonucleotide alone, 6tdG alone or co-injection of thereof, was effective in triggering regression of established 15A tumors with long-term survival of the majority of mice. The effect of CpG(6tdG)-oligonucleotide correlated with the activation of tumor antigen-specific T cell-mediated antitumor immune responses. In contrast, when tested in immunodeficient mice, CpG(6tdG)-oligonucleotide induced significant but transient regression of 15A lymphoma. These results suggest that the oligonucleotide elicits two-pronged activity triggering direct lymphoma cell cytotoxicity and also immune-mediated antitumor effects. Overall, this cell-selective strategy could provide an effective and safer strategy against aggressive TERT+ DLBCL cells with potential to engage and support T cell-based antitumor immunity. Citation Format: Chunsong Yu, Yong Liang, Piotr Swiderski, Larry Kwak, Marcin Kortylewski. Novel targeted oligonucleotide-based telomere disruptor for immunotherapy of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB081.

Abstract Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is associated with an aggressive clinical course and poor survival not to overcome by any standard treatment regimen. We have previously identified a distinct miRNA expression profile in LCT-MF from that of non-transformed MF with significant upregulation of miR-21 and miR-146a. Our analyses demonstrated the involvement of genes for immune checkpoint pathways such as ICOS-ICOSL and PD1-PDL1 signaling (Di Raimondo C et al. Cancers 2021). Here, we aimed to investigate the efficacy of antagomiR-146a and -21 (amiR-146a, and -21) on the tumor growth and CD8+ tumor infiltrating lymphocyte exhaustion in LCT-MF. The amiR-146a, and -21 were synthesized in our DNA/RNA Synthesis Core by linking CpG-D19. In vitro, CTCL cell lines (Myla and HH) were treated with amiR-146a and -21, the cell viability was assessed by the 2,5-diphenyl-2H-tetrazolium bromide assay and cell apoptosis was evaluated using apoptosis assay. We found that amiR-146a, and -21 synergistically inhibited the proliferation of MyLa and HH cells due to the activation of apoptosis through Caspase3/7 pathways and inducing cell cycle arrest by blocking STAT3/CDK1/Cyclin B1 pathway. Our RNA-seq data indicated that the exhausted CD8+ T cells express elevated amounts of STAT3, IRF4, and BATF in LCT-MF compared with non-LCT MF. To evaluate the functional importance of amiR-146a, and -21 on CD8+ T cell exhaustion, we induced an exhausted state of CD8+ T cells with high level of immune checkpoints and dysfunctional cytokine production by continues anti-CD3/DC28 beads and culture supernatant (MyLa or HH cell) exposure. Our data revealed that amiR-146a and -21 attenuated the CD8+ T cell exhaustion by blockade of immune checkpoints and STAT3/IRF4/BATF pathway to trigger the cytotoxic immune response. Collectively, the findings of our study suggest that targeting miR-146a and -21 is a promising and novel therapeutic strategy for LCT-MF. Citation Format: Zhen Han, Piotr Swiderski, Xiwei Wu, Yate-Ching Yuan, Jun Wu, Chingyu Su, Hanjun Qin, Steven Rosen, Christiane Querfeld. Therapeutic targeting miR-146a and miR-21 induce malignant cell death and regulate CD8+ T-cell function in mycosis fungoides with large-cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2907.

Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency in vivo systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide RNA (gRNA) dimers in vitro and in vivo with reduced off-target effects. We show that PS-Cas9/gRNA-mediated gene knockout preserves chimeric antigen receptor T cell viability and expansion in vitro and in vivo. PS-Cas9/gRNA mediates gene perturbation in patient-derived tumor organoids and mouse xenograft tumors, leading to potent tumor antitumor effects. Further, HER2 antibody-PS-Cas9/gRNA conjugate selectively perturbs targeted genes in HER2+ ovarian cancer xenografts in vivo. Moreover, we created bi-specific PS-Cas9 with two gRNAs to target two adjacent sequences of the same gene, leading to efficient targeted gene disruption ex vivo and in vivo with markedly reduced unintended gene perturbation. Thus, the cell-penetrating PS-Cas9/gRNA can achieve efficient systemic delivery and precision in gene disruption.

Decoy oligodeoxynucleotides (ODNs) allow targeting undruggable transcription factors, such as STAT3, but their limited potency and lack of delivery methods hampered translation. To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC). STAT3DPROTAC downregulated STAT3 in target cells, but not STAT1 or STAT5. Computational modeling of the STAT3DPROTAC ternary complex predicted two surface lysines, K601 and K626, in STAT3 as potential ubiquitination sites. Accordingly, K601/K626 point mutations in STAT3, as well as proteasome inhibition or cereblon deletion, alleviated STAT3DPROTAC effect. Next, we conjugated STAT3DPROTAC to a CpG oligonucleotide targeting Toll-like receptor 9 (TLR9) to generate myeloid/B cell-selective C-STAT3DPROTAC. Naked C-STAT3DPROTAC was spontaneously internalized by TLR9+ myeloid cells, B cells, and human and mouse lymphoma cells but not by T cells. C-STAT3DPROTAC effectively decreased STAT3 protein levels and also STAT3-regulated target genes critical for lymphoma cell proliferation and/or survival (BCL2L1, CCND2, and MYC). Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.