Journal for Immunotherapy of Cancer最新文献

{"title":"Reciprocal immune-epithelial interaction during breast cancer induction.","authors":"Neil Carleton, Michael T Lotze","doi":"10.1136/jitc-2024-011453","DOIUrl":"10.1136/jitc-2024-011453","url":null,"abstract":"<p><p>The notion of immune editing and its defined phases (elimination, equilibrium, and escape), once a transformed cell emerges, is now well established. What occurs prior to, and may in fact impact, transformation-inflammation, initiation, and inception of malignancy-has been a murkier proposition. These \"three I's\" form the basis of a concept we put forth called reciprocal learning, which we define as a constant crosstalk in non-diseased tissue between the local epithelial cells and immune cells that occurs across the lifespan. Epithelial cells and resident macrophages provide the basis for genetic and epigenetic alterations as a site for learning by adaptive immune cells. Conversely, epithelial cells learn which changes are recognized by both innate and adaptive immune cells by modulating expression of MHC molecules and the antigen processing and presentation machinery. This \"reciprocal learning\" that occurs between the local epithelium and immune system provides memory for the immune system to then respond to dysregulated epithelial growth across the lifespan. We illustrate this with important recent findings of immune cells within the normal breast. An immune response is most certainly present (surveilling) the breast epithelium from the onset of mammary gland development, during active menstrual cycling, during lactation, and in the postmenopausal period with involution. We speculate that this reciprocal learning may be one of the main reasons why seven out of eight women <i>do not</i> get breast cancer in their lifetime.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HVJ-E links Apolipoprotein d to antitumor effects.","authors":"Airi Ishibashi, Noriko Ohta, Yuko Uegaki, Hidefumi Suzuki, Katsuya Fukino, Yuuta Hisatomi, Atsushi Tanemura, Riuko Ohashi, Koji Kitamura, Kotaro Saga, Yasuhide Yoshimura, Satoko Inubushi, Kyoso Ishida, Yoko Ino, Yayoi Kimura, Kenjiro Sawada, Tadashi Kimura, Eiji Kiyohara, Kosuke Yusa, Hidehisa Takahashi, Yasufumi Kaneda, Keisuke Nimura","doi":"10.1136/jitc-2024-011442","DOIUrl":"10.1136/jitc-2024-011442","url":null,"abstract":"<p><strong>Background: </strong>Virotherapy eradicates tumors by directly killing cancer cells and causing adjuvant effects. However, the mechanism by which non-replicating virotherapy exerts anti-tumor effects is unclear.</p><p><strong>Methods: </strong>In this study, we investigated the genes that mediate the anti-tumor effects of ultraviolet (UV)-irradiated Hemagglutinating Virus of Japan envelope (HVJ-E) using RNA sequencing, gene knockout, and a drug-inducible gene expression system. We examined the antitumor effects of Apolipoprotein d (Apod) using genome-wide CRISPR library screening, in situ biotinylation combined with mass spectrometry, flow cytometry, biochemistry, and tumor-bearing mouse models.</p><p><strong>Results: </strong>Here, we show that HVJ-E represses tumor growth via Irf7-induced Apod expression in tumor cells <i>in vivo</i>. Irf7 in B16F10 cells is a pivotal transcription factor for HVJ-E-induced anti-tumor effects. Apod substantially suppresses tumor growth even in HVJ-E-insensitive tumors. Apod is required to increase NKG2D-ligand genes in HVJ-E-treated tumors. Genome-wide CRISPR library screening and <i>in situ</i> biotinylation of Apod reveal an association of Apod with ERK2. Mechanistically, Apod prevents the nuclear translocation of ERK2 and Importin7, increasing NKG2D-ligands expression in B16F10 cells and attenuating tumor growth. Treating a local tumor with a combination therapy of Apod with the anti-OX40, T cell costimulatory molecule, antibody substantially repressed tumor growth in target and non-target lesions alongside T cell activation.</p><p><strong>Conclusion: </strong>Our findings provide insights into the molecular mechanisms of how HVJ-E induces anti-tumor effects and can aid the development of therapeutic strategies for eliciting anti-tumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Super-high tumor mutational burden predicts complete remission following immunotherapy: from Peto's paradox to druggable cancer hallmark.","authors":"","doi":"10.1136/jitc-2024-010486corr1","DOIUrl":"10.1136/jitc-2024-010486corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 first-in-human dose-escalation study of IMSA101, a novel cyclic di-nucleotide STING agonist, for patients with advanced solid tumor malignancies.","authors":"Jay Jacoby, Deva Mahalingam, Angela Alistar, Edward Garmey, Syed Kazmi, Teresa Mooneyham, Lijun Sun, Timothy A Yap, Peter Vu, Justin Moser","doi":"10.1136/jitc-2025-011572","DOIUrl":"10.1136/jitc-2025-011572","url":null,"abstract":"<p><strong>Background: </strong>Despite progress in cancer therapeutics, there remains an unmet need for treatment of advanced solid tumors. The cGAS-cGAMP-STING pathway plays a pivotal role in innate antitumor immunity processes. IMSA101 is a small molecule analog of cGAMP and a potent STING agonist. Preclinical studies demonstrate antitumor activity of IMSA101 alone and in combination with immune-checkpoint inhibitors (ICIs).</p><p><strong>Methods: </strong>IMSA101-101 was an open-label, multicenter, phase 1 first-in-human dose-escalation study to establish a recommended phase 2 dose (RP2D) of IMSA101 both as monotherapy and in combination with a programmed death ligand 1 (PD-(L)1)-ICI. Secondary objectives were to evaluate safety, tolerability and antitumor activity, and to characterize pharmacokinetics. Adult patients with advanced solid tumors with ≥2 Response Evaluation Criteria in Solid Tumors evaluable lesions, at least one of these suitable for injection, were enrolled. IMSA101 was administered by intratumoral injection with weekly injections for the first 3 weeks, followed by biweekly injections. The dose escalation explored doses of 100-1,200 µg (monotherapy) and 800-2,400 µg (combination therapy with ICI) in a 3+3 design. No formal statistical analysis was planned for this study.</p><p><strong>Results: </strong>40 patients (22 monotherapy, 18 combination therapy) received at least one dose of IMSA101. IMSA101 1,200 µg (monotherapy) and 2,400 µg (combination therapy) doses, well-tolerated and associated with signs of antitumor activity, were selected as provisional RP2Ds. The most common IMSA101-related treatment-emergent adverse events (TEAEs) were injection site pain (8 (36.4%)) and fatigue (4 (18.2%)) for monotherapy and chills (3 (16.7%)), injection site pain (2 (11.1%)), and fever (2 (11.1%)) for combination therapy. No clear dose-response relationship between IMSA101 and occurrence of TEAEs was observed. The elimination half-life of plasma IMSA101 was approximately 1.5-2 hours, with no reported plasma accumulation. With monotherapy, no patients achieved complete response (CR) or partial response (PR), so overall response rate (ORR) was not determined; 17 (77.3%) patients had progressive disease (PD) and one patient (4.5%, 400 µg cohort) had stable disease (SD) as best response. With combination therapy, ORR was 5.6%; remaining patients had PD (10 (55.6%)) and SD (2 (11.1%)) as their best response.</p><p><strong>Conclusions: </strong>IMSA101 doses of 1,200 µg (monotherapy arm) and 2,400 µg (combination therapy arm) were well tolerated but demonstrated minimal signals of antitumor activity in patients with advanced solid tumors.</p><p><strong>Trial registration number: </strong>NCT04020185.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor glyco-immunology, glyco-immune checkpoints and immunotherapy.","authors":"Salomé S Pinho, Matthew S Macauley, Heinz Läubli","doi":"10.1136/jitc-2025-012391","DOIUrl":"10.1136/jitc-2025-012391","url":null,"abstract":"<p><p>Immunotherapy, including immune checkpoint inhibition, has transformed the prognosis of many patients with cancer. However, most patients have primary or secondary resistant tumors to currently available cancer immunotherapies. Changes in glycosylation of malignant cells and in the tumor microenvironment are a new target to overcome resistance to current cancer immunotherapies and to improve the outcome of patients. Here, we summarize how changes in glycosylation in cancer have functional consequences on the immune system. Such changes can be directly targeted with drugs. Moreover, they can mediate immune-suppressive effects. For example, increased sialylation can enhance interactions with immune-inhibitory Siglec receptors, and galectin-mediated interactions can modulate immune responses in the context of cancer. Finally, we provide an overview of approaches to therapeutically target these changes for the improvement of cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12182193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144325773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blockade of colon cancer metastasis via single and double silencing of <i>PCSK7</i>/<i>PCSK9</i>: enhanced T cells cytotoxicity in mouse and human.","authors":"Chloé Porcheron, Mailys Le Devehat, Anna Roubtsova, Hadi Bayat, Alexandra Evagelidis, Leila Jafarzadeh, Vatsal Sachan, Nathalie Labrecque, Alexie Fonta Holder, Delia Susan-Resiga, Rachid Essalmani, Gabrielle Boudreau, Annik Prat, Rebecca Cusseddu, Jean-François Côté, Abdel-Majid Khatib, Jean-Sébastien Delisle, Nabil G Seidah","doi":"10.1136/jitc-2024-011364","DOIUrl":"https://doi.org/10.1136/jitc-2024-011364","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy approaches based on T cells provided breakthroughs in cancer treatment but could cause many immune-related adverse events, and their efficacy is limited for many cancers with an acquired dysfunction/exhaustion of T cells. The present study presents a novel role in immunity for proprotein convertase subtilisin-kexin 7 (PCSK7), the seventh proprotein convertase of the 9-membered secretory proprotein convertase subtilisin-kexin (PCSK)-family.</p><p><strong>Methods: </strong>We analyzed cell surface levels of various immune checkpoint proteins in human and mouse cell models in the presence or absence of PCSK7 expression. Injection of mouse colon carcinoma MC38 cells in the spleen of mice lacking either <i>Pcsk7</i>, <i>Pcsk9</i> or both (double knockout) allowed the analysis of the extent of hepatic tumor metastasis. We also estimated the cell surface expression of checkpoint proteins in CD4⁺ and CD8⁺ T cells from healthy human subjects in which <i>PCSK7</i> expression was silenced by CRISPR Cas9 gRNA knockdown.</p><p><strong>Results: </strong>Bioinformatic and cellular studies showed enrichment of PCSK7 mRNA levels in CD8⁺ T cells, which correlates with those of immune checkpoint proteins (ICPs; eg, <i>LAG3</i>, <i>CTLA4</i>, <i>PD1</i> and <i>TIGIT</i>) responsible for T-cell dysfunction. Indeed, cells lacking PCSK7 and CD8⁺ T cells derived from <i>Pcsk7</i> ^-/- mice exhibited ≥40% lower cell-surface levels of ICPs. Similarly, CRISPR-Cas9 editing of <i>PCSK7</i> (<i>PCSK7</i>i) in primary human T cells resulted in lower expression of ICPs and a reduced proportion of cells expressing multiple ICPs, without altering the expression of activation markers. Moreover, proprotein convertase subtilisin-kexin 9 (PCSK9), the ninth PCSK family member, enhances the degradation of the low-density lipoprotein-receptor and major histocompatibility complex-I proteins. Indeed, <i>Pcsk9</i> ^-/- mice were previously reported to exhibit reduced liver tumor metastasis. In the present studies, we report synergistic and complementary functions of PCSK7 and PCSK9, as the loss of each one of the convertases reduced by twofold the number of liver metastases, but the strongest reduction (>90%) was observed in double KO (<i>Pcsk7</i> ^-/-, <i>Pcsk9</i> ^-/-) mice. In <i>Pcsk7</i> ^-/- mouse tumors the antitumorigenic activity of CD8⁺ T cells was enhanced and the levels of ICPs were reduced.</p><p><strong>Conclusions: </strong>Cumulatively, our data provide a <i>PCSK7</i>i strategy to reduce the levels of cell-surface ICPs, thereby rationalizing the use of <i>PCSK7</i>i in T-cell immunotherapies alone or in combination with a PCSK9 inhibitor/silencer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with PI3K/AKT/mTOR signal signature.","authors":"Xindi Wang, Wenjing Luo, Zhaozhao Chen, Chenggong Li, Jie Zhou, Zhongpei Huang, Lu Tang, Jianghua Wu, Zhuolin Wu, Yingying Li, Yinqiang Zhang, Yun Kang, Qiaolin Liu, Jia Xu, Wei Xiong, Jun Deng, Heng Mei, Yu Hu","doi":"10.1136/jitc-2024-010822","DOIUrl":"https://doi.org/10.1136/jitc-2024-010822","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has demonstrated safety and feasibility in clinical settings; however, limited efficacy due to intrinsic dysfunction and extrinsic suppression remains an unresolved issue. T cells provide multifaceted support to NK cell-mediated responses. Here, we aimed to design a novel CD19-targeted CAR-NK, engineered with secreted interleukin-15 and C-C motif chemokine ligand 21 (ie, 15×21 CAR-NK), capable of recruiting and cooperating with T cells.</p><p><strong>Methods: </strong>We characterized 15×21 CAR-NK cells by performing experiments in vitro and in mouse models, and conducting RNA sequencing.</p><p><strong>Results: </strong>15×21 CAR-NK cells exhibit strong capabilities in cytotoxicity, cytokine production, effector molecule expression, and T-cell recruitment in vitro. Cooperation with T cells promoted efficient tumor-cell elimination, alleviated mutual exhaustion phenotypes, and enhanced the expression of effector molecules/receptors. The recruitment and cooperative effects also result in effective tumor control in mouse models. In addition, 15×21 CAR-NK cells strongly enrich the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway - a key intracellular signaling cascade that is associated with enhanced downstream pro-survival signaling, anti-apoptotic ability, mitochondrial function, and cytotoxicity.</p><p><strong>Conclusions: </strong>Our study highlights the intrinsic advantages and extrinsic T-cell cooperative benefits of 15×21 CAR-NK cells, providing a promising strategy for NK-cell-based immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary on \"Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors\".","authors":"Marc Lecoultre, Aya El Helali","doi":"10.1136/jitc-2025-012218","DOIUrl":"https://doi.org/10.1136/jitc-2025-012218","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs), long exploited by cancers to evade immune detection, can now be reprogrammed into potent antitumor effectors through cutting-edge viral engineering. In a landmark study published in the <i>Journal for Immunotherapy of Cancer</i>, Zhang <i>et al</i> introduced an innovative adenovirus, Adv-mSS, that blocks two critical \"don't eat me\" signals, CD47 and CD24, used by tumors to paralyze macrophage activity. By converting immunosuppressive TAMs into tumor-engulfing predators and reigniting CD8 T-cell response, Adv-mSS eradicated tumors across multiple preclinical models. This strategy offers a promising avenue for activating both innate and adaptive immunity against cancer and may address key limitations of current immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma.","authors":"Rebekah E Dadey, Ruxuan Li, Jake Griner, Jie Chen, Arjun Singh, Brian Isett, Sarah Newman, Ryan Augustin, Aofei Li, Joseph A Manning, Satdarshan P Monga, Aatur Singhi, David A A Geller, Carsten Krieg, Ioannis K Zervantonakis, Jason John Luke, Riyue Bao","doi":"10.1136/jitc-2025-011537","DOIUrl":"10.1136/jitc-2025-011537","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have improved patient outcomes in hepatocellular carcinoma (HCC); however, most patients do not experience durable benefit. The non-T cell-inflamed tumor microenvironment, characterized by limited CD8⁺ T-cell infiltration, reduced dendritic cell function, and low interferon-γ-associated gene expression, is associated with a lower likelihood of response to ICI. To nominate new therapeutic targets for overcoming ICI resistance in HCC, we conducted a large-scale multiomic analysis on 900+human specimens (RNA sequencing (RNA-seq), proteomics) and 31 tumor single-cell (sc) RNA-seq samples, with tissue validation through imaging mass cytometry (IMC) and spatial lipidomics by matrix-assisted laser desorption/ionization (MALDI), with experimental investigation by in vitro CD8⁺ T-cell recruitment and macrophage polarization functional assays using three-dimensional (3D) co-culture models. We discovered 32 oncogenic pathways associated with immune exclusion, with sterol regulatory element binding protein 1 (SREBP1, encoded by <i>SREBF1</i>) as a hub regulator. scRNA-seq analysis showed that SREBP1 signaling is associated with enriched lipid biogenesis pathways in tumor cells, elevated immunosuppressive markers in macrophages, and diminished CD8⁺ T-cell infiltration. Integration of IMC and MALDI images revealed distinct lipid species differentially abundant in tumor regions with low versus high CD8⁺ T cell infiltration. Functional studies in a 3D in vitro tumor-immune co-culture system demonstrated that CRISPR-mediated <i>SREBF1</i> knockout (KO) in HepG2 cells reduced monocyte recruitment, decreased expression of the protumorigenic CD206 marker in macrophages, and enhanced CD8⁺ T-cell migration compared with wild-type (WT) (p<0.0001). RNA-seq of <i>SREBF1</i> KO versus WT tumor cells confirmed suppression of lipid biosynthesis genes.Our findings nominate an atlas of tumor-intrinsic drivers of immune exclusion, particularly SREBP1 via pro-tumorigenic macrophage (M2-like) reprogramming. These pathways may represent novel therapeutic targets to enhance antitumor immunity and deserve further study as targeted therapy candidates to enhance ICI in HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting CMTM4 reverses the immunosuppressive function of myeloid-derived suppressor cells and augments immunotherapy response in cervical cancer.","authors":"Jianyi Ding, Haoran Hu, Yashi Zhu, Xinxin Xu, Bo Yin, Meiqin Yang, Huijuan Zhou, Tiefeng Huang, Mengjie Li, Yifan Kou, Zilale Rahim, Baoyou Huang, Ang Li, Wei Wang, Lingfei Han","doi":"10.1136/jitc-2025-011776","DOIUrl":"10.1136/jitc-2025-011776","url":null,"abstract":"<p><p>CKLF (chemokine-like factor)-like MARVEL transmembrane domain-containing family member 4 (CMTM4), belonging to the CMTM family of transmembrane domain proteins, plays a significant role in the initiation, progression, and metastasis of cancer. Nevertheless, its involvement in tumor immunity remains elusive. In the present investigation, we observed an upregulation of CMTM4 expression in patients with cervical cancer (CC), which also serves as a prognostic indicator for patients with CC. In vitro experiments and therapeutic models have demonstrated that CMTM4 upregulates the expansion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment via the CCL2 (C-C motif chemokine ligand 2)/CCR2 (C-C motif chemokine ligand 2) and IL-6 (interleukin-6)/GP130 (glycoprotein 130) axes. This process exerts immunosuppressive effects and promotes the occurrence and progression of CC. Mechanistically, CMTM4 interacts and stabilizes PHB2 (prohibitin 2) through post-translational modification, which further induces activation of the STING (stimulator of interferon genes)/TBK1 (TANK-binding kinase 1)/STAT6 (signal transducer and activator of transcription 6) pathway, facilitating the nuclear translocation of STAT6 which binds to the CCL2/IL-6 promoter, leading to the upregulation of CCL2/IL-6 transcription expression. Importantly, targeting CMTM4 with CMTM4-small interfering RNA enhanced the effectiveness of anti-programmed cell death protein 1 (anti-PD-1) therapy. Our study identifies CMTM4 as a crucial determinant guiding the homing of MDSCs to CC, thereby contributing to MDSCs-mediated immune suppression and tumor progression. The combination of CMTM4 inhibition and anti-PD-1 treatment shows promising antitumor efficacy against CC. These findings offer novel insights into the tumor microenvironment and have the potential to inform the development of innovative immunotherapy approaches for CC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}