Molecular Cancer Therapeutics最新文献

{"title":"Therapeutic Targeting of BET proteins in Sarcoma.","authors":"Niknam Riyahi, Rada Malko, Harlan E Shannon, Kyle W Jackson, Ryli E Justice, Keiko Kreklau, M Reza Saadatzadeh, Karen E Pollok, Pankita H Pandya","doi":"10.1158/1535-7163.MCT-24-1027","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1027","url":null,"abstract":"<p><p>Bromodomain and extraterminal domain (BET) protein family are epigenetic readers that regulate gene transcription, cell cycle progression, and DNA damage response (DDR), making them attractive therapeutic targets for sarcomas, which are epigenetically dysregulated and genomically unstable. Sarcomas are molecularly heterogeneous with a high propensity for metastasis, resulting in poor clinical outcomes. BET inhibitors (BETi) hold promise for treatment of sarcomas, for they block interaction of BETs with acetylated lysines, modify gene expression, and create an imbalance in transcription and replication kinetics. BETi also disrupt transcriptional programs driven by oncogenic fusion proteins found in some sarcomas. Preclinical studies demonstrate efficacy of BETi in inducing apoptosis, disrupting DDR, and reducing tumor growth, either as monotherapy or in combination with chemotherapy or other targeted agents, such as PI3K, HDAC, and CHK1 inhibitors. Favorable results have been observed in clinical trials, but more studies are required to fully assess safety and efficacy as well as identify biomarkers of response and resistance. Ongoing research is focused on optimizing BETi safety, selectivity, and exploring combination therapies, such as BETi with DDR inhibitors. This review summarizes the preclinical studies on BET inhibition and discusses clinical trial activity, providing insight into the potential of BETi in sarcoma therapy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730524","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":"Enhanced Antitumor Immunity by ASP1570, a Novel Diacylglycerol Kinase Zeta Inhibitor, Offers a Potential Novel Immunotherapy for Treating Cancer.","authors":"Osamu Ikeda, Aya Kikuchi, Hirofumi Tsuzuki, Hideyuki Watanabe, Keiichiro Okuyama, Yohei Seki, Satoru Ujihara, Toshihiro Matsuda, Jane Weng, Tomoko Kawashima, Tetsuo Kiso, Atsushi Suzuki, Takeyuki Nagashima, Tomoyuki Suzuki, Kazuya Yamano, Tatsuya Kawase, Taku Yoshida","doi":"10.1158/1535-7163.MCT-23-0108","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-23-0108","url":null,"abstract":"<p><p>Studies of diacylglycerol kinase ζ (DGKζ) in DGKζ knockout mice have revealed its role as an intracellular immune checkpoint in T cells. Although enhancing antitumor immunity by pharmacological inhibition of DGKζ is desirable, selective DGKζ inhibitors for clinical use remain largely unexplored. Here, we report a novel, small-molecule, DGKζ inhibitor, ASP1570, which is currently under phase 1 development (NCT05083481), and characterize its effect on potential resistance mechanisms against approved immune checkpoint inhibitors in multiple immunosuppressive conditions: not only TGF-β, PGE2, adenosine, PD-1, but also CTLA-4 and TIGIT. Firstly, our findings indicated that ASP1570 exhibited an inhibitory effect on the kinase activity of DGKζ. Unexpectedly, we observed that DGKζ protein was degraded in cells treated with ASP1570 in a proteasome-dependent manner. ASP1570 enhanced T-cell activation with increased diacylglycerol downstream signaling and released anergic T cells from their hyporesponsive state. Further, ASP1570 restored T-cell functions suppressed by multiple immunosuppressive signals (TGF-β, PGE2, adenosine, PD-1, CTLA-4, and TIGIT) and induced tumor growth inhibition in 2 types of syngeneic mouse models: anti-PD-1-antibody-sensitive MC38 and anti-PD-1-antibody-insensitive B16F1/F10. The antitumor efficacy of ASP1570 was cancelled by CD8+ T-cell depletion, indicating that its antitumor effect depends on CD8+ cytotoxic T-cell activation. Collectively, ASP1570 potentially improves antitumor efficacy in both anti-PD-1-therapy-resistant and anti-PD-1-therapy-responsive tumors by overcoming multiple immunosuppressive signals.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730523","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":"Repurposing the DNA Labeling Agent EdU for Therapy Against Heterogeneous Patient Glioblastoma.","authors":"Humeyra Kaanoglu, Adebimpe Adefolaju, Casey Fraley, Mariah Shobande, Rajaneekar Dasari, Breanna Mann, Noah Bell, Stephen T Keir, Dominique Higgins, David E Kram, Shawn D Hingtgen, Aziz Sancar, Andrew B Satterlee","doi":"10.1158/1535-7163.MCT-24-1098","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-1098","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common type of malignant central nervous system tumor and more than 300,000 people are diagnosed with GBM worldwide annually. Based on its recognition as damage by nucleotide excision repair, we now repurpose the DNA labeling agent 5-ethynyl-2'-deoxyuridine (EdU) as a treatment for GBM. We tested the efficacy of EdU in several different model systems, including not only GBM cell lines in in vitro cell culture and in vivo orthotopic mouse models of GBM, but also against living, uncultured GBM patient tumor tissues grown within our Organotypic Brain Slice Culture (OBSC) ex vivo platform. When compared to the standard of care drug Temozolomide (TMZ) in in vitro GBM cell survival assays, EdU displayed ED50 values orders of magnitude lower than TMZ in all five GBM tumor lines tested. Against two in vivo orthotopic brain tumor models, EdU significantly extended survival relative to controls. EdU efficacy against a panel of patient GBMs largely correlated with the clinical Ki-67 status of each tumor, save for one tumor that remained unresponsive to treatment with both EdU and TMZ. Overall, these data suggest that (1) EdU has potential to be repurposed as an anticancer therapeutic and is especially adept at killing rapidly proliferating cells with low off-target toxicity; (2) the OBSC platform can measure nuanced differences in efficacy of experimental therapeutics on heterogeneous patient tumor tissues; and (3) OBSCs can continue to help identify potential responders and non-responders to EdU treatment via functional precision testing of patient tumors ex vivo.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700569","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":"Epigenetic Regulation of Cellular Senescence in Gastrointestinal Cancer.","authors":"Ting Ye, Hang Gao, Zheng-Rong Zhang, Yang Ge, Yi-Ke Liu, Jing-Yuan Yan, De-Yi Li, Feng-Yuan Chen, Hang Song","doi":"10.1158/1535-7163.MCT-24-0949","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0949","url":null,"abstract":"<p><p>Gastrointestinal (GI) cancers, encompassing malignancies of the digestive tract, are significant contributors to global cancer morbidity and mortality. Despite advancements in molecular insights and therapeutic approaches, the prognosis remains dismal due to persistent treatment resistance and metastasis. Cellular senescence, a permanent halt in the cell cycle due to various stressors, playing dual roles in tumor suppression and promotion. Interestingly, epigenetic modifications-heritable shifts in gene level without altering the DNA sequence-are identified as key regulators of cellular senescence. These modifications, such as DNA methylation, histone alterations, chromatin remodeling, and non-coding RNA interactions, shape the senescence phenotype and influence cancer progression and therapy resistance. Recent research underscores the potential of \"pro-senescence\" therapies, leveraging epigenetic modulators and senescence-inducing agents to counteract GI cancer progression. This review explores the relationship between cellular senescence and epigenetic regulation in the context of GI cancer highlighting the characteristics of senescence, the epigenetic mechanisms at play, their impact on GI cancer senescence, and the promising horizon of anti-senescence therapies. Through a detailed examination of current research, we propose that understanding the intricacies of epigenetic regulation in cellular senescence offers a novel vista for therapeutic intervention in GI cancers, potentially paving the way for improved clinical outcomes.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700610","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":"Heterogeneous Responses to High-Dose Testosterone in Castration-Resistant Prostate Cancer Tumors with Mixed Rb-Proficient and Rb-Deficient Cells.","authors":"Maryam Labaf, Wanting Han, Songqi Zhang, Mingyu Liu, Nolan D Patten, Muqing Li, Susan Patalano, Jill A Macoska, Steven P Balk, Dong Han, Kourosh Zarringhalam, Changmeng Cai","doi":"10.1158/1535-7163.MCT-24-0716","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0716","url":null,"abstract":"<p><p>Androgen deprivation therapy remains a cornerstone in managing prostate cancer. However, its recurrence often leads to the more aggressive castration-resistant prostate cancer (CRPC). Although second-line androgen receptor signaling inhibition treatments such as enzalutamide and abiraterone are available, their effectiveness against CRPC is only transient. High-dose testosterone (Hi-T) has recently emerged as a promising treatment for CRPC, primarily through the suppression of E2F and MYC signaling. However, the roles of Rb family proteins in influencing this therapeutic response remain debated. In this study, we utilized a CRPC patient-derived xenograft model that includes both Rb pathway-proficient and -deficient cell populations based on the positive or negative expression of RB family genes. Single-cell RNA sequencing analysis revealed that Rb-proficient cells displayed a robust response to Hi-T, whereas Rb-deficient cells exhibited significant resistance. Notably, our analysis indicated increased enrichment of the hypoxia signature in the Rb-deficient cell population. Further studies in RB1-silenced CRPC cell lines showed that treatment with a hypoxia-inducible factor-1α inhibitor can restore the sensitivity of Rb-deficient cells to high-dose dihydrotestosterone treatment. In conclusion, our research provides new molecular insights into CRPC tumor cell responses to Hi-T and proposes a new strategy to resensitize Rb-deficient CRPC cells to Hi-T treatment.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":5.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673367","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":"18F-FLT PET, a Non-Invasive Pharmacodynamic Biomarker of Tumor Cell Proliferation, Detected Differential Response to Various Cyclin Dependent Kinase (CDK) Inhibitors.","authors":"Anand Giddabasappa, Ziyue Karen Jiang, Bing Yang, Laigao Chen, Feng Liu, Edward Cabral, Sripad Ram, Britton Boras, Nanni Huser, Cathy C Zhang, Kavon Noorbehesht, Lisa K Manzuk, Ravi Visswanathan, Sepideh Mojtahedzadeh, Timothy Affolter, Jason Carmody, Aubrey Nayeon Kang, Matthew D Petroski, Penney Lai Khamphavong, Todd VanArsdale, Quang-De Nguyen, Kevin P Maresca, Stephen G Dann","doi":"10.1158/1535-7163.MCT-24-0856","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0856","url":null,"abstract":"<p><p>A dysregulated cell cycle is a hallmark of cancer and inhibition of cyclin dependent kinases (CDKs) is a proven therapeutic strategy in treating HR+/HER2- breast cancer and a variety of other cancers. 18F-FLT (18F-3'-deoxy-3'-fluorothymidine) is a validated positron emission tomography (PET) biomarker to measure cell proliferation. Here we show the utility of 18F-FLT PET imaging as a pharmcodynamic (PD) biomarker in differentiating the efficacy of PF-07104091 (CDK2 selective inhibitor) in Palbociclib (CDK4/6 inhibitor) sensitive and resistant tumor models. 18F-FLT PET imaging was performed after 4 days of treatment with CDK inhibitors and immunohistochemistry (IHC) biomarkers of tumor cell proliferation (Ki67 and pRb) were evaluated for correlation. Tumor growth inhibition (TGI) studies demonstrated that Palbociclib was efficacious in MCF7 model, but not in OVCAR-3 model, whereas PF-07104091 showed dose-dependent TGI in both MCF7 and OVCAR-3 models. Consistent with this observation, 18F-FLT PET was able to differentiate the resistance to Palbociclib from sensitivity to PF-06873600 (CDK2/4/6 inhibitor) and PF-07104091 in OVCAR-3 model. In contrast, 18F-FLT PET biomarker showed reduced uptake in MCF7 model after treatment with both Palbociclib and PF-07104091. Similarly, PF-07104091 demonstrated reduced 18F-FLT uptake in the NIBR-5493, an ovarian cancer PDX model. IHC biomarkers, Ki67 and pRb correlated with the 18F-FLT uptake trends in all three tumor models. This work highlights the utility of 18F-FLT PET as a quantitative, non-invasive biomarker which provides whole-body information. 18F-FLT PET has potential to be a biomarker in novel CDK inhibitor clinical trials to evaluate Palbociclib resistance and identifying responding and non-responding patients.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673366","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":"Advances in antibody-drug conjugates for endometrial cancer.","authors":"Pan Tu, Gaofeng Li, Wen Zou, Chao Xu, Jingjing Wang","doi":"10.1158/1535-7163.MCT-24-0763","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0763","url":null,"abstract":"<p><p>The treatment of advanced endometrial cancer is clinically challenging, prompting the exploration of innovative therapeutic strategies such as antibody-drug conjugates (ADCs). ADCs, which include monoclonal antibodies, cytotoxic components, and linkers, demonstrate robust targeting, cytotoxicity, and manageable adverse effects. To provide a thorough understanding of the status of research, this review elucidates promising therapeutic targets in endometrial cancer, such as HER2, FRα, and TROP-2, and summarizes preclinical and clinical trial data on related ADC drugs in endometrial cancer. We also discuss the toxicity of ADC drugs. Most adverse events arise from cytotoxic components such as microtubule inhibitors and topoisomerase inhibitors. The ocular toxicity may be mainly related to off-target effects of MMAF/DF4 payloads. Interstitial lung disease (ILD) is a serious adverse event, mainly caused by antibodies, and most of them are grade 1-2 toxicity. Among them, anti-HER2 ADC induced interstitial pneumonia is commonly dose dependent. Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663723","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":"Development of a Tumor-Specific Multivalent CD40 Agonist Antibody FAPxCD40 for Cancer Therapy: Balancing Efficacy and Toxicity.","authors":"Simeng Chen, Yuan Lin, Dan Li, Xiaoru Zhou, Xing Sun, Changyong Yang, Cheng Liao","doi":"10.1158/1535-7163.MCT-24-0717","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0717","url":null,"abstract":"<p><p>CD40 agonist antibodies are reported to augment tumor antigen presentation and have shown potential anti-tumor efficacy in clinical trials. Nevertheless, the limited efficacy and on-target, off-tumor toxicity restrict the further development of these antibodies. We hypothesize that the toxicity could be overcome by activating CD40 specifically through tumor-specific antigens. Additionally, limited efficacy can be improved through the strategic construction of CD40 bispecific antibodies (bsAbs) to refine the degree of CD40 clustering. Therefore, we developed anti-FAPxCD40 bsAbs with varying valences of anti-CD40 moieties, including bivalent FAPxCD40-2, tetravalent FAPxCD40-4, and hexavalent FAPxCD40-6. The tetravalent design of FAPxCD40-4 led to efficient activation of antigen-presenting cells and T cell priming in the presence of FAP. The antitumor activity and toxicity of FAPxCD40-4 were tested in the CD40 humanized mFAP-MC38 xenograft model. Compared to non-tumor-targeting CD40 agonist or bivalent bispecific antibodies, FAPxCD40-4 displayed potent anti-tumor activity and negligible toxicity at low doses, indicating an ideal therapeutic window. Our results demonstrated that the valences of the anti-CD40 moieties in bsAbs can be modulated to optimize CD40 activation and enlarge the therapeutic window of this type of molecules.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663843","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":"Co-inhibition of Aurora kinase B and SUV4-20H induces synthetic lethality in Wild-type p53 deficient cancer cells.","authors":"Lei Duan, Kelsey M O'Hara, Andrew Caldemeyer, Carl G Maki","doi":"10.1158/1535-7163.MCT-24-0928","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0928","url":null,"abstract":"<p><p>The tumor suppressor p53 is inactivated by mutation or deletion in over half of all human cancers. Wild-type p53 induces a G1-phase arrest when activated to halt cell proliferation and division. Accordingly, p53 mutated or deficient cancers may be especially sensitive to agents that target proliferating and/or dividing cells. Barasertib (AZD2811) targets the mitotic kinase Aurora B (AURKB) and is in current clinical trials for various cancers. SUV4-20H1 and H2 are histone methyltransferases that can affect mitosis by regulating chromatin compaction in and around centromeres. The drug A196 inhibits SUV4-20H1 and H2. In the current study, we found combined treatment with barasertib plus A196 induces a pronounced synthetic lethality effect in p53-deficient cancer cells. Mechanistically, we found barasertib plus A196 kills p53-deficient cells by inhibiting the spindle assembly checkpoint and inducing massive chromosome missegregations and toxic aneuploidy. Among breast cancer sub-types, triple negative breast cancer cells were the most sensitive to this drug combination. Lastly, we found in two different p53 mutated cell line tumor models that barasertib plus A196 has greater anti-tumor activity than either single agent. Our results suggest co-targeting of AURKB and SUV4-20H1/2 could be effective against p53-mutated or deficient cancers, including TNBCs in which approximately 80% of cases are p53 mutated.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657827","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":"Histotripsy-focused ultrasound treatment abrogates tumor hypoxia responses and stimulates anti-tumor immune responses in melanoma.","authors":"Brian Song, Heineken Queen, Sarah F Ferris, Reliza McGinnis, Chaitanya Karanam, Natalie Gatteno, Katherine Buglak, Hanna Kim, Jintao Xu, Kristie D Goughenour, Zhen Xu, Michal A Olszewski, Clifford S Cho, Anutosh Ganguly","doi":"10.1158/1535-7163.MCT-24-0715","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-24-0715","url":null,"abstract":"<p><p>Histotripsy focused ultrasound treatment gives rise to systemic anti-tumor immune responses. We investigated whether histotripsy effects on immunosuppressive tumor hypoxia were a potential mechanism for these immunostimulatory effects. Immunocompetent or CD8-deficient C57BL/6 mice with flank B16F10 or YUMM1.7 melanoma tumors underwent sham or subtotal histotripsy. Tumor growth, immune cell infiltration, and intratumoral hypoxia responses were examined using flow cytometry and fluorescence microscopy. Chemokine receptor CXCR3 and hypoxia-inducible factor-1α (HIF-1α) were intercepted with antibodies and inhibitors to assess their roles in immune responses post-histotripsy. Histotripsy-treated tumors exhibited rapid loss of intratumoral hypoxia and suppression of HIF-1α and downstream pro-survival proteins. Histotripsy was followed by intratumoral upregulation of the CXCR3 ligand CXCL10, and CXCR3+/CD8+ T cell infiltration. Tumor growth inhibition by histotripsy was significantly diminished in CD8-deficient mice and mice receiving anti-CXCR3 mAb. Post-histotripsy inhibition of hypoxia and tumor growth eventually receded in parallel with cessation of CD8+ T cell influx, and pharmacological HIF-1α suppression with the MEK inhibitor Trametinib substantially augmented the therapeutic effects of histotripsy. Transient abrogation of intratumoral hypoxia and HIF-1α-associated hypoxia responses is mechanistically linked with intratumoral infiltration of activated CXCR3+/CD8+ T cells via CXCL10:CXCR3 engagement. These findings suggest that the immune effects of histotripsy may be regulated by hypoxia abrogation, and that pharmacological hypoxia abrogation could potentiate the immunotherapeutic effects of histotripsy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657829","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}