Molecular Cancer Therapeutics最新文献

{"title":"Tumor Integrin-Targeted Glucose Oxidase Enzyme Promotes ROS-Mediated Cell Death that Combines with Interferon Alpha Therapy for Tumor Control.","authors":"Jordan A Stinson, Allison Sheen, Brianna M Lax, Grace N Yang, Lauren Duhamel, Luciano Santollani, Elizabeth Fink, Joseph R Palmeri, Karl Dane Wittrup","doi":"10.1158/1535-7163.MCT-24-0163","DOIUrl":"10.1158/1535-7163.MCT-24-0163","url":null,"abstract":"<p><p>Although heightened intratumoral levels of reactive oxygen species (ROS) are typically associated with a suppressive tumor microenvironment, under certain conditions ROS contribute to tumor elimination. Treatment approaches, including some chemotherapy and radiation protocols, increase cancer cell ROS levels that influence their mechanism of cell death and subsequent recognition by the immune system. Furthermore, activated myeloid cells rapidly generate ROS upon encounter with pathogens or infected cells to eliminate disease, and recently, this effector function has been noted in cancer contexts as well. Collectively, ROS-induced cancer cell death may help initiate adaptive antitumor immune responses that could synergize with current approved immunotherapies, for improved control of solid tumors. In this work, we explore the use of glucose oxidase, an enzyme which produces hydrogen peroxide, a type of ROS, to therapeutically mimic the endogenous oxidative burst from myeloid cells to promote antigen generation within the tumor microenvironment. We engineer the enzyme to target pan-tumor-expressed integrins both as a tumor-agnostic therapeutic approach and as a strategy to prolong local enzyme activity following intratumoral administration. We found the targeted enzyme potently induced cancer cell death and enhanced cross-presentation by dendritic cells in vitro and further combined with interferon alpha for long-term tumor control in murine MC38 tumors in vivo. Optimizing the single-dose administration of this enzyme overcomes limitations with immunogenicity noted for other prooxidant enzyme approaches. Overall, our results suggest ROS-induced cell death can be harnessed for tumor control and highlight the potential use of designed enzyme therapies alongside immunotherapy against cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"118-130"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Tumor Antigen 5T4 Using CAR T Cells for the Treatment of Acute Myeloid Leukemia.","authors":"Richard Harrop, Daniel G Blount, Naeem Khan, Mayowa Soyombo, Laura Moyce, Mark T Drayson, Jenny Down, Michelle A Lawson, Deirdre O'Connor, Rachael Nimmo, Yatish Lad, Bernard Souberbielle, Kyriacos Mitrophanous, Anna Ettorre","doi":"10.1158/1535-7163.MCT-24-0052","DOIUrl":"10.1158/1535-7163.MCT-24-0052","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and subsequently eradicate tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step for a targeted therapy that selectively targets cancer cells without affecting normal tissues. 5T4 is a tumor-associated antigen expressed on the cell surface of most solid tumors. However, very little is known about its expression in hematologic malignancies. In this study, we assess the expression of 5T4 in different types of leukemias, specifically acute myeloid leukemia (AML), and normal hematopoietic stem cells (HSC). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR T cells against HSCs and AML tumor cell lines. 5T4 expression was seen in about 50% of AML cases; AML with mutated nucleophosmin 1, AML-myelodysplasia-related, and AML not otherwise specified showed the highest percentage of 5T4+ cases. 5T4 CAR T cells efficiently and specifically killed AML tumor cell lines, including leukemic stem cells. Coculture of 5T4 CAR T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A proof-of-concept study using a murine model for AML demonstrated that CAR T cells recognize 5T4 expressed on cells and can kill tumor cells both in vitro and in vivo. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR T cells can be considered a powerful personalized therapeutic approach to treat AML.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"93-104"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells.","authors":"Jay M Gamma, Qiang Liu, Erwan Beauchamp, Aishwarya Iyer, Megan C Yap, Zoulika Zak, Cassidy Ekstrom, Rony Pain, Morris A Kostiuk, John R Mackey, Joseph Brandwein, Jean C Y Wang, Luc G Berthiaume","doi":"10.1158/1535-7163.MCT-24-0307","DOIUrl":"10.1158/1535-7163.MCT-24-0307","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a hematologic malignancy with limited treatment options and a high likelihood of recurrence after chemotherapy. We studied N-myristoylation, the myristate modification of proteins linked to survival signaling and metabolism, as a potential therapeutic target for AML. N-myristoylation is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2, with varying expressions in AML cell lines and patient samples. We identified NMT2 expression as a marker for survival of patients with AML, and low NMT2 expression was associated with poor outcomes. We used the first-in-class pan-NMT inhibitor, zelenirstat, to investigate the role of N-myristoylation in AML. Zelenirstat effectively inhibits myristoylation in AML cell lines and patient samples, leading to degradation of Src family kinases, induction of endoplasmic reticulum stress, apoptosis, and cell death. Zelenirstat was well tolerated in vivo and reduced the leukemic burden in an ectopic AML cell line and in multiple orthotopic AML patient-derived xenograft models. The leukemia stem cell-enriched fractions of the hierarchical OCI-AML22 model were highly sensitive to myristoylation inhibition. Zelenirstat also impairs mitochondrial complex I and oxidative phosphorylation, which are critical for leukemia stem cell survival. These findings suggest that targeting N-myristoylation with zelenirstat represents a novel therapeutic approach for AML, with promise in patients with currently poor outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"69-80"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Discovery of a Potent PARP1 Inhibitor Senaparib.","authors":"Sui X Cai, Ning Ma, Xiaozhu Wang, Mingchuan Guo, Yangzhen Jiang, Ye E Tian","doi":"10.1158/1535-7163.MCT-23-0625","DOIUrl":"10.1158/1535-7163.MCT-23-0625","url":null,"abstract":"<p><p>PARP1 is a critical enzyme involved in DNA damage repair. It belongs to a superfamily of proteins and catalyzes poly(ADP-ribosyl)ation (PARylation). PARP1 inhibitors are effective to treat tumors that have homologous recombination deficiency such as those with BRCA1/2 mutations. The PARP1 inhibitors that have been approved by FDA inhibit both PARP1 and PARP2. PARP2 has also been suggested to play a similar function in DNA repair as PARP1. In addition to inhibiting PARP1 enzymatic activities, PARP1 inhibitors cause the PARP1 enzyme to be \"trapped\" on DNA, stalling the DNA replication fork and eventually causing double-strand DNA breaks and cell death. Here, we report a PARP1 inhibitor, Senaparib, which has a novel chemical structure and high potency inhibiting PARP1/2 enzymes. Senaparib was highly potent in cell viability tests against tumor cells with BRCA1/2 mutations. It was efficacious in cell line-derived and patient-derived xenograft models in tumors harboring BRCA1/2 mutations. In combination studies, Senaparib used with temozolomide had shown strong synergistic cytotoxicity in both in vitro and in vivo experiments. Senaparib represents a novel class of PARP1 inhibitors that can be used for the treatment of cancer. A phase III clinical study of Senaparib for maintenance treatment following first-line chemotherapy in patients with advanced ovarian cancer has met its primary endpoint, and a new drug application of Senaparib has been accepted by the National Medical Products Administration of China for review.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"47-55"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Inhibition of the Met Receptor Tyrosine Kinase Signaling Enhances the Chemosensitivity of Glioma Cell Lines to CDDP Through Activation of p38 MAPK Pathway.","authors":"Xiuqin Lou, Qibing Zhou, Ying Yin, Cheng Zhou, Yan Shen","doi":"10.1158/1535-7163.MCT-24-0974","DOIUrl":"10.1158/1535-7163.MCT-24-0974","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"152"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Looking Beyond Checkpoint Inhibitor Monotherapy: Uncovering New Frontiers for Pancreatic Cancer Immunotherapy.","authors":"Eileena F Giurini, Oliver Ralph, Sam G Pappas, Kajal H Gupta","doi":"10.1158/1535-7163.MCT-24-0311","DOIUrl":"10.1158/1535-7163.MCT-24-0311","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) stands out as one of the most aggressive and challenging tumors, characterized by a bleak prognosis with a mere 11% survival rate over 5 years in the United States. Its formidable nature is primarily attributed to its highly aggressive behavior and poor response to existing therapies. PDAC, being notably resistant to immune interventions, presents a significant obstacle in treatment strategies. While immune checkpoint inhibitor therapies have revolutionized outcomes for various cancers, their efficacy in PDAC remains exceedingly low, benefiting less than 1% of patients. The consistent failure of these therapies in PDAC has prompted intensive investigation, particularly at the preclinical level, to unravel the intricate mechanisms of resistance inherent in this cancer type. This pursuit aims to pave the way for the development of novel immunotherapeutic strategies tailored to the distinct characteristics of PDAC. This review endeavors to provide a comprehensive exploration of these emerging immunotherapy approaches in PDAC, with a specific emphasis on elucidating their underlying immunological mechanisms. Additionally, it sheds light on the recently identified factors driving resistance to immunotherapy and evasion of the immune system in PDAC, offering insights beyond the conventional drivers that have been extensively studied.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"18-32"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PET Imaging Using 89Zr-Labeled StarPEG Nanocarriers Reveals Heterogeneous Enhanced Permeability and Retention in Prostate Cancer.","authors":"Niranjan Meher, Anil P Bidkar, Anju Wadhwa, Kondapa Naidu Bobba, Suchi Dhrona, Chandrashekhar Dasari, Changhua Mu, Cyril O Y Fong, Juan A Cámara, Umama Ali, Megha Basak, David Bulkley, Veronica Steri, Shaun D Fontaine, Jun Zhu, Adam Oskowitz, Rahul R Aggarwal, Renuka Sriram, Jonathan Chou, David M Wilson, Youngho Seo, Daniel V Santi, Gary W Ashley, Henry F VanBrocklin, Robert R Flavell","doi":"10.1158/1535-7163.MCT-24-0024","DOIUrl":"10.1158/1535-7163.MCT-24-0024","url":null,"abstract":"<p><p>The enhanced permeability and retention (EPR) effect controls passive nanodrug uptake in tumors and may provide a high tumor payload with prolonged retention for cancer treatment. However, EPR-mediated tumor uptake and distribution vary by cancer phenotype. Thus, we hypothesized that a companion PET imaging surrogate may benefit EPR-mediated therapeutic drug delivery. We developed two 89Zr-radiolabeled nanocarriers based on 4-armed starPEG40kDa with or without talazoparib (TLZ), a potent PARP inhibitor, as surrogates for the PEG-TLZ4 therapeutic scaffold. For PET imaging, PEG-DFB4 and PEG-DFB1-TLZ3 were radiolabeled with 89Zr by replacing one or all four copis of TLZ on PEG-TLZ4 with deferoxamine B (DFB). The radiolabeled nanodrugs [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 were tested in vivo in prostate cancer subcutaneous (s.c.) xenografts (22Rv1, LTL-545, and LTL-610) and 22Rv1 metastatic models. Their EPR-mediated tumoral uptake and penetration was compared with CT26, a known EPR-high cell line. MicroPET/CT images, organ biodistribution, and calculated kinetic parameters showed high uptake in CT26 and LTL-545 and moderate to low uptake in LTL-610 and 22Rv1. MicroPET/CT and high-resolution autoradiographic images showed nanocarrier penetration into highly permeable CT26, but heterogeneous peripheral accumulation was observed in LTL-545, LTL-610, and 22Rv1 s.c. xenografts and metastatic tumors. CD31 staining of tumor sections showed homogenous vascular development in CT26 tumors and heterogeneity in other xenografts. Both [89Zr]PEG-DFB4 and [89Zr]PEG-DFB1-TLZ3 showed similar accumulation and distribution in s.c. and metastatic tumor models. Both nanocarriers can measure tumor model passive uptake heterogeneity. Although heterogeneous, prostate cancer xenografts had low EPR. These starPEG nanocarriers could be used as PET imaging surrogates to predict drug delivery and efficacy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"141-151"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-Specific Antigen Delivery for T-cell Therapy via a pH-Sensitive Peptide Conjugate.","authors":"Annali M Yurkevicz, Yanfeng Liu, Samuel G Katz, Peter M Glazer","doi":"10.1158/1535-7163.MCT-23-0809","DOIUrl":"10.1158/1535-7163.MCT-23-0809","url":null,"abstract":"<p><p>Identifying an optimal antigen for targeted cancer therapy is challenging as the antigen landscape on cancerous tissues mimics that of healthy tissues, with few unique tumor-specific antigens identified in individual patients. pH low insertion peptide (pHLIP) acts as a unique delivery platform that can specifically target the acidic microenvironment of tumors, sparing healthy tissue in the process. We developed a pHLIP-peptide conjugate to deliver the SIINFEKL peptide, an immunogenic fragment of ovalbumin (OVA), to tumor cells in vivo. When processed intracellularly, SIINFEKL is presented for immune recognition through the major histocompatibility complex (MHC) class I pathway. We observed selective delivery of pHLIP-SIINFEKL both in vitro and in vivo using fluorescently labeled constructs. In vitro, treatment of melanoma tumor cells with pHLIP-SIINFEKL resulted in recognition by SIINFEKL-specific T cells (OT1), leading to T-cell activation and effector function. Mechanistically, we show that this recognition by OT1 T cells was abrogated by siRNA/shRNA knockdown of multiple components within the MHC class I pathway in the target tumor cells, indicating that an intact antigen processing pathway in the cancer cells is necessary to mediate the effect of pHLIP-directed SIINFEKL delivery. In vivo, pHLIP-SIINFEKL treatment of tumor-bearing mice resulted in the recruitment of OT1 T cells and suppression of tumor growth in two syngeneic tumor models in immunocompetent mice, with no effect when mutating either the pHLIP or SIINFEKL components of the conjugate. These results suggest that pHLIP-mediated peptide delivery can be used to deliver novel artificial antigens that can be targeted by cell-based therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"105-117"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Lipid Nanoparticle NBF-006 Encapsulating Glutathione S-Transferase P siRNA for the Treatment of KRAS-Driven Non-small Cell Lung Cancer.","authors":"Cima Cina, Bharat Majeti, Zhihong O'Brien, Li Wang, Jean Pierre Clamme, Roger Adami, Kwok Yin Tsang, Jens Harborth, Wenbin Ying, Sonya Zabludoff","doi":"10.1158/1535-7163.MCT-23-0915","DOIUrl":"10.1158/1535-7163.MCT-23-0915","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, and KRAS mutations occur in 25% to 30% of NSCLC. Our approach to developing a therapeutic with the potential to target KRAS-mutant NSCLC was to identify a new target involved in modulating signaling proteins in the RAS pathway. Glutathione S-transferase P (GSTP), known as a phase II detoxification enzyme, has more recently been identified as a modulator of MAPK-related cell signaling pathways. Therefore, developing a GSTP siRNA may be an effective therapeutic approach to treat KRAS-mutant NSCLC. The lead drug product candidate (NBF-006) is a proprietary siRNA-based lipid nanoparticle comprising GSTP siRNA (NDT-05-1040). Here, studies using a panel of KRAS-mutant NSCLC cell lines demonstrated that NDT-05-1040 is a very potent and selective GSTP siRNA inhibitor. Our Western blot analysis showed that NDT-05-1040 effectively decreased the phosphorylation of MAPK and PI3K pathway components while upregulating apoptotic signaling cascade. Our in vivo studies revealed statistically significant higher distribution of NBF-006 to the lungs and tumor as compared with the liver. In the subcutaneous and orthotopic tumor models, NBF-006 led to a statistically significant and dose-dependent antitumor growth inhibition. Furthermore, quantitative image analysis of proliferating cell nuclear antigen and PARP staining showed that NBF-006 decreased proliferation and induced apoptosis, respectively, in tumors. Additionally, in a surgically implanted orthotopic lung tumor model, the survival rate of the NBF-006 treatment group was significantly prolonged (P < 0.005) as compared with the vehicle control group. Together, these preclinical studies supported advancement of NBF-006 into clinical studies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"7-17"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Riluzole Enhancing Anti-PD-1 Efficacy by Activating cGAS/STING Signaling in Colorectal Cancer.","authors":"Beiyuan Liang, Misbah Khan, Hayden Storts, Evan H Zhang, Xinru Zheng, Xuanxuan Xing, Hazel Claybon, Jenna Wilson, Chunjie Li, Ning Jin, Richard Fishel, Wayne O Miles, Jing J Wang","doi":"10.1158/1535-7163.MCT-24-0289","DOIUrl":"10.1158/1535-7163.MCT-24-0289","url":null,"abstract":"<p><p>Colorectal cancer is the second leading cause of cancer mortality in the United States. Although immune checkpoint blockade therapies including anti-PD-1/PD-L1 have been successful in treating a subset of patients with colorectal cancer, the response rates remain low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune-competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway in colon cancer cells, resulting in increased expression of IFNβ and IFNβ-regulated genes including CXCL10. Inhibition of ataxia telangiectasia mutated (ATM), but not ATM-related, resulted in a synergistic increase in IFNβ expression, suggesting that riluzole induces ATM-mediated damage response that contributes to cGAS/STING activation. Depletion of cGAS or STING significantly attenuated riluzole-induced expression of IFNβ and CXCL10 as well as increase of intratumoral CD8+ T cells and suppression of tumor growth. These results indicate that riluzole-mediated tumor infiltration of CD8+ T cells and attenuation of tumor growth is dependent on tumor cell-intrinsic STING activation. To determine whether riluzole treatment primes the tumor microenvironment for immune checkpoint modulation, riluzole was combined with anti-PD-1 treatment. This combination showed greater efficacy than either single agent and strongly suppressed tumor growth in vivo. Taken together, our studies indicate that riluzole activates cGAS/STING-mediated innate immune responses, which might be exploited to sensitize colorectal tumors to anti-PD-1/PD-L1 therapies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"131-140"},"PeriodicalIF":5.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}