Norman AO, Scaramella C, Biezonski D
… +10 more, Hector RD, Varallo A, Sahni A, Farooq N, Burstein SR, Benito J, Razak KA, Selfridge J, Cobb S, Ethell IM
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42389555
·
Full text
Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the () gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinan...Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the () gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.
St-Denis-Bissonnette F, Mediratta K, Ho N
… +10 more, Kirkby M, Stalker A, Muradia G, Shrestha A, Ardolino M, Lee SH, Burger D, Mer A, Wang L, Lavoie JR
Mol Ther Oncol
· 2026 Sep · PMID 42383255
·
Full text
Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (...Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (EVs), which transfer molecular signals between cells and influence immune function. Although NK cell-derived EVs (NK92-EVs) have shown the ability to directly kill cancer cells, how they shape the broader human immune response has remained unclear. Here, NK92-EVs were shown to reprogram cellular human immunity to enhance tumor cytotoxicity using single-cell transcriptomics and functional cytotoxicity assays. When human peripheral blood mononuclear cells (PBMCs) from healthy and cancer patients (who exhibit systemic dysregulation) were exposed to NK92-EVs, widespread shifts in gene activity occurred across key immune populations, notably CD8 T cells and NK cells. These changes enhanced the cells' ability to recognize and eliminate tumor targets and were consistent across all donors. Functional depletion and enrichment experiments, together with transcriptomic profiling, provide direct evidence that NK92-EV-mediated immune reprogramming enhances NK cell-driven, MHC-I-independent tumor cytotoxicity, but not for CD4 and CD8 T cells. This work advances understanding of immune communication and highlights NK92-EVs as promising, cell-free candidates for the next generation of cancer immunotherapies that unite potency with clinical scalability.
Bragato N, Dias AB, Ohradanova-Repic A
… +15 more, Dupanovic A, Horvat F, Fischer P, Appel LM, Walch L, Kleinwächter A, Röhrer A, Kerschbaum-Gruber S, Barna S, Fossati P, Georg D, Widder J, Podar K, Cohen M, Slade D
Mol Ther Oncol
· 2026 Sep · PMID 42383254
·
Full text
Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer with a poor prognosis and resistance to conventional radio- and chemotherapy. Radiation can induce pro-inflammatory signaling by acti...Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer with a poor prognosis and resistance to conventional radio- and chemotherapy. Radiation can induce pro-inflammatory signaling by activating the type 1 interferon (IFN-I) response, which can be enhanced by targeting negative regulators of the IFN-I pathway, such as ADP-ribosyltransferase PARP7. Here, we show that PARP7 inhibitors (PARP7i) enhance radiation-induced cell death and promote STING- and NF-κB-dependent immunogenic signaling in PDAC cells, leading to inflammatory gene expression and cytokine release. These effects were most pronounced in BxPC-3 cells, which exhibit higher baseline expression of , , and interferon response genes. PARP7i potentiated the immunogenic effects of hypofractionated radiation by inducing a STING-dependent IFN-I response, leading to immunogenic cell death and activation of monocytes and NK cells. Carbon ion irradiation elicited stronger immunogenicity than X-rays when combined with PARP7i. KRAS-mutated PANC-1 cells showed a higher expression of enzymes that convert ATP to immunosuppressive adenosine, which was enhanced by radiation. This may explain why PARP7i were more effective as monotherapy in PANC-1 cells, promoting NK cell activation. These findings support further evaluation of PARP7i in PDAC in combination with radiotherapy or as monotherapy, depending on the immunosuppressive effects of radiation.
Vermeer C, Venema RR, Birnie E
… +4 more, Bolling MC, Knoers N, Bremer J, van den Akker PC
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381708
·
Full text
Antisense oligonucleotides (ASOs) are increasingly being used as a platform to target various diseases. Currently, there are 13 USFDA- or EMA-approved ASO therapies. Adverse events resulting from ASO treatments are asses...Antisense oligonucleotides (ASOs) are increasingly being used as a platform to target various diseases. Currently, there are 13 USFDA- or EMA-approved ASO therapies. Adverse events resulting from ASO treatments are assessed on a per drug basis, but for many ongoing ASO developments targeting N-of-1 mutations, conventional randomized clinical trials to assess safety cannot be performed. Here, we conducted a systematic review and meta-analysis of adverse events in clinical studies conducting trials of ASO therapies. The study aims to provide better insight into the safety aspects of ASO design choices and to summarize knowledge of the safety aspects of ASOs so that we can better inform researchers and physicians of possible adverse events that can occur during (N-of-1) ASO treatments. Our results provide a list of common adverse events and event rates obtained from pooled data from both approved and non-approved ASO drugs, and we include recommendations that can provide insights into the nature of ASO-induced adverse events in future trials.
Ju S, Lee JH, Yang J
… +10 more, Jeong TY, Choi CG, Lee Y, Cha S, Park J, Kim SP, Kim S, Seong JK, Lee H, Kim K
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381707
·
Full text
Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome and epigenome editing hold great promise for precision therapy, yet their clinical translation is limited by delivery challenges. Here, we p...Clustered regularly interspaced short palindromic repeats (CRISPR)-based genome and epigenome editing hold great promise for precision therapy, yet their clinical translation is limited by delivery challenges. Here, we present a transient, DNA-free virus-like particle (VLP) platform for the delivery of CRISPR ribonucleoprotein (RNP) across diverse cancer applications. VLP-mediated genome editing achieved high editing efficiency and broad applicability across multiple cancer types. Notably, VLP-mediated mutation-selective targeting of oncogenic alleles induced potent on-target activity and high-fidelity mutation-selective effects in cancer cells, with minimal effects on normal cells. Beyond genome editing, VLP delivery of the epigenome editor CRISPRoff effectively suppressed cancer cell growth and induced stable gene silencing maintained for over 120 days. Moreover, it provided a strategy to overcome knockout escape, a key limitation of conventional genome editing. In comparison with DNA vector-based delivery systems, VLPs enabled transient expression while achieving lower off-target activity and higher efficiency. Furthermore, the VLP platform exhibited a favorable safety profile, characterized by transient exposure and no hepatotoxicity. In a mouse xenograft model, the platform successfully suppressed tumor growth via precision targeting. Collectively, these findings establish VLP-mediated CRISPR delivery as a versatile and safe integrated delivery platform, providing a comprehensive modality for both genome and epigenome editing in precision therapeutics.
Karimi S, Dehpour AR, Hadjighassem M
… +5 more, Khajehnasiri A, Yekta RA, Aghaei M, Majedi H, Hosseindoost S
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381706
·
Full text
Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor. Its clinical management is challenging due to its heterogeneity, highly malignant nature, and insensitivity to standard treatments. While c...Glioblastoma multiforme (GBM) is the most malignant type of primary brain tumor. Its clinical management is challenging due to its heterogeneity, highly malignant nature, and insensitivity to standard treatments. While current strategies for GBM treatments are based on inducing apoptosis in GBM cells, some GBM tumors showed resistance to this type of cell death. Recent evidence indicates that pyroptosis is a novel, promising therapeutic method for overcoming tumor cells' resistance to cancer treatment. This inflammatory programmed cell death type is mediated by the cleavage of gasdermin proteins. Based on the evidence, inducing pyroptosis is negatively associated with GBM growth and development; the exact molecular mechanisms and the signaling pathways underlying pyroptosis are not fully understood. This review presents the different pathways of pyroptosis and its role in GBM growth regulating and illustrates various drugs and components that modulate pyroptosis in GBM tumors. It also investigates the regulatory roles of noncoding RNAs in pyroptosis modulation in GBM tumors, providing promising therapeutic approaches that target pyroptosis as a novel strategy for GBM treatment.
Kunrade L, Pleiko K, Sproge L
… +7 more, Goluba K, Pantelejevs T, Wright NT, Akopjana I, Bogans J, Tars K, Riekstina U
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381705
·
Full text
Malaria remains a major global health concern. The development of point-of-care diagnostic aptasensors could improve malaria detection, patient management, and eradication efforts. We selected and validated single-strand...Malaria remains a major global health concern. The development of point-of-care diagnostic aptasensors could improve malaria detection, patient management, and eradication efforts. We selected and validated single-stranded DNA aptamers against lactate dehydrogenase (Pf-LDH), using systematic evolution of ligands by exponential enrichment (SELEX). The five most abundant aptamers were validated with an enzyme-linked oligonucleotide assay (ELONA). The aptamer binding affinities to Pf-LDH varied between 0.35 and 3.08 nM. Truncation of aptamers enhanced binding affinities in most cases, with all truncated aptamers showing comparable or improved dissociation constants (Kd) relative to full-length aptamers, except Pf-LDH5t, which lost its binding affinity. Selectivity analysis against LDH from , , and showed that Pf-LDH1 and Pf-LDH1t specifically recognized Pf-LDH (Kd = 2.74 ± 0.28 and 1.13 ± 0.26 nM, respectively), while Pf-LDH2, Pf-LDH3, Pf-LDH4, and their truncated forms, as well as Pf-LDH5, recognized both Pf-LDH and LDH (Po-LDH). Crystallography of Pf-LDH4t revealed a binding site overlapping that of the previously characterized aptamer 2008 but involving distinct molecular interactions. These findings demonstrate the structural versatility of LDH-specific aptamers and provide a novel Pf- and Po-LDH co-specific aptamer panel with strong potential for next-generation aptamer-based malaria diagnostics.
Samuels TN, Kakadia JH, Ward C
… +11 more, Abdullatif F, Mendes MI, Smith DE, Heilmann R, Wu F, Swiercz JM, Salamons GS, Hoffman K, Gebregiworgis T, O'Donoghue P, Heinemann IU
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381704
·
Full text
Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to...Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.
Li CG, Sun Q, Tian T
… +8 more, Wu ZC, Xie YC, Liu XQ, Zhou ZR, Huang LX, Deng XH, Yu SL, Fu QL
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42381703
·
Full text
Previous studies have demonstrated that miR-146a-5p can effectively inhibit the function of group 2 innate lymphoid cells (ILC2s), which play a pivotal role in the initiation of allergic airway inflammation (AAI), thereb...Previous studies have demonstrated that miR-146a-5p can effectively inhibit the function of group 2 innate lymphoid cells (ILC2s), which play a pivotal role in the initiation of allergic airway inflammation (AAI), thereby alleviating AAI. However, the application of miR-146a-5p faces challenges such as susceptibility to degradation and difficulty in crossing the cellular membrane. Extracellular vesicles (EVs), which naturally transport proteins and nucleic acids, have been proposed as promising RNA delivery vehicles. EVs can protect microRNAs (miRNAs) from degradation and facilitate their penetration across cellular membranes. However, the lack of scalable sources of EVs remains a challenge for their mass production, particularly in clinical application. Bovine milk has emerged as an advantageous source for the large-scale production of EVs because of its low cost and easy accessibility. Moreover, bovine milk-derived EVs (mEVs) have shown low immunogenicity and outstanding cross-species biosafety. In this study, we present the manufacturing methods and immune regulatory effects of mEVs loaded with miR-146a-5p (miR146a-5p-mEVs). Our findings indicated that mEVs exhibited outstanding biosafety and did not elicit significant systemic toxicity. Importantly, miR146a-5p-mEVs exhibited significant immunoregulatory functions in AAI, suggesting that miR146a-5p-mEVs could serve as a novel strategy for the treatment of allergic airway disease.
Phillips MA, Lei L, Kulhankova K
… +6 more, Gingerich MC, Loza LM, Vu A, He B, Thornell IM, McCray PB
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42376650
·
Full text
Parainfluenza virus 5 (PIV5)-derived amplifying virus-like particles (PIV5-AVLPs) are an efficient gene delivery platform with broad cell tropism. To investigate the feasibility of using PIV5-AVLPs for cystic fibrosis (C...Parainfluenza virus 5 (PIV5)-derived amplifying virus-like particles (PIV5-AVLPs) are an efficient gene delivery platform with broad cell tropism. To investigate the feasibility of using PIV5-AVLPs for cystic fibrosis (CF) gene therapy, we generated AVLPs expressing enhanced green fluorescent protein (AVLP-eGFP) or a codon-optimized human cystic fibrosis transmembrane conductance regulator () coding sequence and an reporter (AVLP-CFTR). We examined the transduction efficiency and persistence of transgene expression of AVLP-eGFP in primary cultures of non-CF and CF human airway epithelia (HAE). When applied to the apical surface of HAE, the AVLP-eGFP mainly transduced ciliated epithelial cells, with lesser targeting to secretory and basal cells. Reporter transgene expression gradually diminished over a 1-month time course. Transducing approximately 15% of CF airway epithelial cells with AVLP-CFTR was sufficient to restore CFTR-dependent short-circuit current to levels similar to non-CF epithelia. Our results demonstrate that PIV5-AVLPs delivered to the apical side of HAE efficiently transduce sufficient epithelial cells to restore functional CFTR expression. PIV5-based AVLPs provide a versatile platform for the delivery of a variety of genetic cargoes to the respiratory tract.
Antignani G, Feodoroff M, Chiaro J
… +26 more, Feola S, Russo S, Hamdan Hissaoui F, Fusciello M, D'Alessio F, Bottega P, Giannoula Y, Sakalauskaite M, Sandberg J, Kosonen M, Stigzelius V, Luck TJ, Ferrari V, Ciampi D, Haapala M, Branca RM, Partanen J, Koskela S, Rescigno M, Sikanen T, Lehtiö J, Ndika J, Kari OK, Pietiäinen VM, Grönholm M, Cerullo V
Mol Ther Oncol
· 2026 Sep · PMID 42375394
·
Full text
Immunotherapy has revolutionized cancer treatment, yet clinical success remains limited, with only a fraction of patients responding. Tumor heterogeneity and patient-specificity hinder response prediction, emphasizing th...Immunotherapy has revolutionized cancer treatment, yet clinical success remains limited, with only a fraction of patients responding. Tumor heterogeneity and patient-specificity hinder response prediction, emphasizing the need for human-based models that accurately reproduce tumor-immune interactions. Conventional preclinical platforms, such as murine models, lack the human-specific HLA-TCR complexity, limiting their ability to accurately evaluate immunotherapy responses. To address this, we established a patient-specific pipeline for precision immunotherapy in renal cell carcinoma (RCC) and bladder cancer (BC). Tumor and adjacent tissues were used to generate patient-derived tumor organoids (PDTOs) and patient-derived cells (PDCs) for immunopeptidome profiling. Using our in-house microfluidic platform, PeptiCHIP, we identified tumor-associated HLA-I peptides as potential T cell targets. Their immunogenicity was evaluated using peptide-expanded, HLA-matched peripheral blood mononuclear cells (PBMCs), revealing peptides capable of inducing antigen-specific CD8 T cell activation and cytotoxicity against the patient's tumor. This study integrates PDCs, immunopeptidomics, and functional immune assays to design and test personalized cancer immunotherapies. By recreating patient-specific tumor-immune interactions , our platform enables the discovery of therapeutic targets, the evaluation of immune responses, and validation in a patient-specific context. This approach demonstrates the feasibility of bridging a major gap in translational immunotherapy research and supports the development of personalized cancer immunotherapy strategies.
Cutmore LC, Lam N, Amatya C
… +4 more, Weissler KA, Hewitt SM, Natrakul DA, Kochenderfer JN
Mol Ther Oncol
· 2026 Sep · PMID 42375393
·
Full text
T cell malignancies expressing γδ T cell receptors (TCRs) have poor prognoses. No approved treatments specifically target γδ T cell malignancies. To address this deficiency, we aimed to develop chimeric antigen receptors...T cell malignancies expressing γδ T cell receptors (TCRs) have poor prognoses. No approved treatments specifically target γδ T cell malignancies. To address this deficiency, we aimed to develop chimeric antigen receptors (CARs) targeting the γδ TCR. We generated a panel of CARs with variations in antigen-recognition domains, hinge and transmembrane (HTM) domains, and costimulatory domains. We expressed CARs in human T cells by γ-retroviral transduction. By assessing CAR T cell cytokine release in response to γδ TCR-expressing target cells, we identified two single-chain variable fragments (scFvs) with superior antigen specificity for the γδ TCR. CARs containing one of the two scFvs, which was designated maximal gamma-delta-long (MGDL), exhibited higher transduction efficiency. We compared three MGDL-containing CARs: MGDL-28Z (CD28 HTM and costimulatory domains), MGDL-CD828Z (CD8α HTM domains and CD28 costimulatory domain), and MGDL-CD8BBZ (CD8α HTM domains and 4-1BB costimulatory domain). Levels of antigen-specific cytokine release were higher for T cells expressing MGDL-28Z compared with the other MGDL CARs. We tested T cells expressing the three MGDL-containing CARs in two murine γδ T cell leukemia treatment models. MGDL-28Z-expressing T cells caused the most anti-leukemia activity and longest mouse survival. These findings support testing MGDL-28Z-expressing T cells in a clinical trial.
Vafaeinik F, Narayanasamy B, Helmueller S
… +7 more, Zhang Y, Gangi A, Lee H, Song C, Figlin R, Sargsyan K, Lee YJ
Mol Ther Oncol
· 2026 Sep · PMID 42371539
·
Full text
Hepatic colorectal metastases, also termed colorectal liver metastases (CRLM), remain a major clinical challenge, despite advances in surgery and chemotherapy. The complexity of CRLM pathology necessitates novel therapeu...Hepatic colorectal metastases, also termed colorectal liver metastases (CRLM), remain a major clinical challenge, despite advances in surgery and chemotherapy. The complexity of CRLM pathology necessitates novel therapeutic approaches, yet current preclinical models often fail to accurately recapitulate the human tumor microenvironment. To overcome these limitations, we utilized patient-derived three-dimensional (3D) CRLM tumoroids to evaluate the efficacy of DZ-1-DHA, a novel conjugate consisting of the heptamethine carbocyanine dye DZ-1 linked to the anti-malarial derivative dihydroartemisinin (DHA). Data from TUNEL and immunoblotting assays revealed that treatment of CRLM tumoroids with DZ-1-DHA led to significant tumor cell death, accompanied by apoptotic signaling. Fluorescence imaging with MitoTracker, 2',7'-dichlorofluorescin diacetate, MitoSOX, and JC-1 showed that DZ-1-DHA accumulates in mitochondria, where it induces generation of cytotoxic reactive oxygen species (ROS) and causes mitochondrial membrane depolarization. Furthermore, data from treatment with deferoxamine or MitoTEMPO indicated that DZ-1-DHA promotes mitochondrial ROS production through a Fenton-like mechanism. These findings demonstrate that DZ-1-DHA triggers apoptosis through mitochondrial stress and apoptotic signaling pathways. Also, DZ-1-DHA represents a promising second-line therapeutic strategy for CRLM. By inducing selective tumor cell death through mitochondrial-targeted apoptosis in a clinically relevant 3D model. This promising approach needs validation for safety and efficacy.
King E, Saha C, Saleem R
… +5 more, Jiang B, O'Donoghue E, Cottone F, McCarthy HO, Piskareva O
Mol Ther Oncol
· 2026 Jun · PMID 42369018
·
Full text
Neuroblastoma is an aggressive pediatric solid tumor that arises during embryonic development and contributes to 15% of cancer-related deaths in children. To date, neither experimental nor clinical trial data on an mRNA...Neuroblastoma is an aggressive pediatric solid tumor that arises during embryonic development and contributes to 15% of cancer-related deaths in children. To date, neither experimental nor clinical trial data on an mRNA vaccine for neuroblastoma have been published, highlighting a significant gap in the anticancer vaccine development pipeline. This study presents the first mRNA vaccine for the treatment of neuroblastoma. We explored the self-assembling peptide RALA for delivering mRNA encoding glypican 2 (GPC2), a potent tumor-associated antigen in neuroblastoma. These data outline rigorous characterization of vaccine nanoparticle formulations, cellular uptake, and functionality. Immunization of mice with RALA/ generated an antigen-specific cellular immune response against GPC2, with significant increases in IFN-γ and IL-2 expression by splenocytes and TNF-α expression by CD4 and CD8 T cells. Immunization delayed tumor development by 10-11 days and reduced tumor volume by 70% compared with unvaccinated controls in a subcutaneous murine model of -amplified neuroblastoma. This work demonstrates the therapeutic potential of the RALA/ vaccine for treating neuroblastoma. Additionally, GPC2 is upregulated across multiple adult and pediatric cancer subtypes, establishing this vaccine as an attractive immunotherapy with far-reaching potential.
Ikoma T, Araki K, Kitagawa M
… +17 more, Makihara N, Nagata Y, Fujii K, Okuno Y, Kamisako K, Okazaki Y, Nakanishi K, Sanada Y, Yoshida K, Nakahama K, Takeyasu Y, Katsushima U, Yamanaka Y, Ikeda S, Yoshioka H, Shimizu T, Kurata T
Mol Ther Oncol
· 2026 Sep · PMID 42368624
·
Full text
Angiotensin II receptor type 1 () has emerged as a potential modulator of the tumor microenvironment, yet its role in the immunotherapy response in non-small cell lung cancer (NSCLC) remains unclear. We performed a compr...Angiotensin II receptor type 1 () has emerged as a potential modulator of the tumor microenvironment, yet its role in the immunotherapy response in non-small cell lung cancer (NSCLC) remains unclear. We performed a comprehensive analysis using bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) datasets. Functional validation included IHC for and phospho-SMAD2/3 co-localization. The clinical impact of angiotensin receptor blocker (ARB) use was assessed in patients receiving immune checkpoint blockade (ICB) alone or combined with chemo-immunotherapy. -high expression in NSCLC was associated with pronounced pathway modulation, including significant upregulation of TGF-β, etc. scRNA-seq analysis revealed that was predominantly localized in cancer-associated fibroblasts (CAFs). IHC validation in NSCLC specimens ( = 14) demonstrated a strong correlation between stromal AGTR1 and phospho-SMAD2/3 expression and ARB-treated patients showed significantly reduced stromal and pSMAD2/3 expression. Clinically, ARB treatment showed no benefit in ICB monotherapy but significantly improved PFS in chemo-immunotherapy (HR = 0.70, = 0.01), especially in non-squamous (non-Sq) histology with PD-L1≥1% (HR = 0.52, = 0.01). AGTR1 is predominantly expressed in CAFs and is suggestive of a correlation with TGF-β-related immunosuppressive features in NSCLC. The combination of ARB with chemo-immunotherapy may enhance therapeutic efficacy through targeting that axis in CAFs, specifically in non-Sq NSCLC patients.
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42367247
·
Full text
Innate immunity plays a vital role in subverting viral infections via dynamic regulatory networks that calibrate antiviral response and prevent excessive inflammation. These networks are coordinately regulated by coding...Innate immunity plays a vital role in subverting viral infections via dynamic regulatory networks that calibrate antiviral response and prevent excessive inflammation. These networks are coordinately regulated by coding and non-coding elements of the genome. The non-coding elements, particularly circular RNAs (circRNAs), have emerged as a key modulator of various biological processes, yet their precise function in innate immune response during influenza A virus (IAV) infection remains insufficiently defined. Here, we identified circCPSF6, a conserved circRNA that remains suppressed during IAV infection, and . Functional analyses revealed that circCPSF6 acts as an antiviral regulator through a dual regulatory mechanism of RNA-RNA and RNA-protein interactions. circCPSF6 sponges proviral miR-665, thereby alleviating the repression of key antiviral mediators such as MyD88, STAT2, and IKKε via RNA-RNA interactions. At RNA-protein level, circCPSF6 directly interacts with the RNA-binding protein PCBP2, which is a negative regulator of IPS-1, and sustains IPS-1-mediated antiviral signaling. These interactions enhance cytokines and interferon-stimulated genes expression, which strengthen antiviral response. Our findings report circCPSF6 as a crucial regulator of host innate immune response and highlight circRNA-mediated networks as potential therapeutic targets in viral infection.
Kwon JE, Kim YJ, Kim SH
… +9 more, Kwon OS, Jang HK, Choi YM, Na HJ, Han N, Chun Y, Han JW, Park TK, Chung KS
Mol Ther Nucleic Acids
· 2026 Sep · PMID 42367246
·
Full text
Inherited retinal diseases (IRDs) are major causes of vision loss and often associated with the degeneration of retinal neurons, such as photoreceptors. Adeno-associated virus (AAV) vectors hold therapeutic potential for...Inherited retinal diseases (IRDs) are major causes of vision loss and often associated with the degeneration of retinal neurons, such as photoreceptors. Adeno-associated virus (AAV) vectors hold therapeutic potential for IRDs; however, their off-target expression has prompted the development of refined engineering strategies to enhance cell-type preference without compromising transgene expression. Here, we present G5mP, a streamlined 315-bp synthetic promoter-enhancer construct designed for robust retinal gene expression. G5mP integrates three components: G5, a G protein-coupled receptor kinase 1-derived enhancer; mP, a minimal promoter from phosphodiesterase 6B; and a 5'-untranslated region (UTR) derived from retinoschisin 1 (RS1). Compared with the clinically used 742-bp RIR cassette-comprising the RS1 promoter, interphotoreceptor retinoid-binding protein enhancer, and RS1-derived 5'-UTR-G5mP drove stronger overall retinal expression and showed enhanced activity within photoreceptor cells in retinal cell lines, human retinal organoids, and mouse retina without inducing detectable cytotoxicity . Notably, across retinal cell lines, human retinal organoids, and mouse retina, G5mP induced more robust and distinct photoreceptor-preferential transgene expression than the ubiquitous CAG promoter did. These results highlight its potential as a compact and efficient regulatory element suitable for AAV-mediated gene delivery across retinal cell types, including the effective targeting of photoreceptors.