Journal Articles

Loss of the autoimmune risk gene TREX1 reveals a convergence of mechanisms promoting immune tolerance loss and antitumor immunity Spotlight 

Junghyun Lim 1, Katherine Williams 1, Stephanie Mittman 1, Patricia Pacheco Sanchez 1, Ryan Rodriguez 1, Annie Ogasawara 1, Grace Barnett 1, Mayra Cruz Tleugabulova 1, Barzin Y Nabet 1, Jeffrey Hung 1, Kevin A Marroquin 1, Shari Lau 1, Serena Y Lee 1, Paul Tyler 1, Elizabeth T Carbone 1, Bridget Hough 1, Janice Corpuz 1, Haruka Murota 1, Edward Dere 1, Smadar Shiffman 1, Leah K Schutt 1, Herman Gill 1, Julia Lau 1, Marco De Simone 1, Lucinda Tam 1, Merone Roose-Girma 1, Søren Warming 1, Soyoung A Oh 1, Sascha Rutz 1, Meng Xiao He 1, Sören Müller 1, Nathaniel R West 1, Thomas F Brewer 1, Prashant Desai 1, Simon Williams 1, James Ziai 1, Yan Qu 1, Klaus Heger 1

Science advances | Free PMC Article

As certain irAEs correlate with clinical efficacy following checkpoint inhibitor therapy, Lim and Williams et al. investigated the relationship between autoimmunity and antitumor immunity. Loss of TREX1, an autoimmune risk gene and key negative regulator of the STING and type I IFN pathways promoted antitumor immunity in mice, and shared pathways with successful cancer immunotherapy. Like in PDCD1-/- and CTLA4-/- mice, constitutive TREX1 loss resulted in multiorgan CD8+ T cell influx, autoimmunity, and myocarditis. Conditional systemic TREX1 ablation was well tolerated and promoted effective CD8+ T cell-driven antitumor immunity, suggesting a new opportunity for immunotherapy.

Contributed by Katherine Turner

Junghyun Lim 1, Katherine Williams 1, Stephanie Mittman 1, Patricia Pacheco Sanchez 1, Ryan Rodriguez 1, Annie Ogasawara 1, Grace Barnett 1, Mayra Cruz Tleugabulova 1, Barzin Y Nabet 1, Jeffrey Hung 1, Kevin A Marroquin 1, Shari Lau 1, Serena Y Lee 1, Paul Tyler 1, Elizabeth T Carbone 1, Bridget Hough 1, Janice Corpuz 1, Haruka Murota 1, Edward Dere 1, Smadar Shiffman 1, Leah K Schutt 1, Herman Gill 1, Julia Lau 1, Marco De Simone 1, Lucinda Tam 1, Merone Roose-Girma 1, Søren Warming 1, Soyoung A Oh 1, Sascha Rutz 1, Meng Xiao He 1, Sören Müller 1, Nathaniel R West 1, Thomas F Brewer 1, Prashant Desai 1, Simon Williams 1, James Ziai 1, Yan Qu 1, Klaus Heger 1

Science advances | Free PMC Article

As certain irAEs correlate with clinical efficacy following checkpoint inhibitor therapy, Lim and Williams et al. investigated the relationship between autoimmunity and antitumor immunity. Loss of TREX1, an autoimmune risk gene and key negative regulator of the STING and type I IFN pathways promoted antitumor immunity in mice, and shared pathways with successful cancer immunotherapy. Like in PDCD1-/- and CTLA4-/- mice, constitutive TREX1 loss resulted in multiorgan CD8+ T cell influx, autoimmunity, and myocarditis. Conditional systemic TREX1 ablation was well tolerated and promoted effective CD8+ T cell-driven antitumor immunity, suggesting a new opportunity for immunotherapy.

Contributed by Katherine Turner

ABSTRACT: Checkpoint inhibitors targeting PD-1 and CTLA-4 have transformed cancer therapy. Both are genetically associated with autoimmune disorders. Moreover, certain immune-related adverse events and autoimmune risk variants are linked to the clinical efficacy of checkpoint inhibition. These associations suggest common principles governing successful cancer immunotherapy and autoimmune susceptibility. Here, we show that ablation of the cytosolic DNA exonuclease TREX1 predisposes mice to autoimmunity while promoting robust antitumor immunity. Constitutive TREX1 loss leads to early onset autoimmunity, characterized by multiorgan CD8+ T cell infiltration, myocarditis, and Sjgren's syndrome-like disease. In contrast, induced systemic TREX1 ablation is well tolerated and promotes effective CD8+ T cell-driven antitumor immunity. Detailed phenotypic studies revealed a notable overlap between productive antitumor and pathogenic autoimmune CD8+ T cell responses. Collectively, we provide mechanistic evidence for interrelated mechanisms underlying autoimmunity and successful cancer immunotherapy, uncover key parallels between adaptive T cell and innate immune checkpoints, and suggest that targeting autoimmune risk genes represents a promising future avenue for cancer immunotherapy.

Author Info: 1Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Author Info: 1Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Citation: Sci Adv 2026 May 8 12:eaea6842 Epub05/06/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42090506

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    Tumors hijack immune-privileging regulons via distinct cell types to confer T cell desertion and immunotherapy resistance across various cancers Spotlight 

    Bashir Lawal 1 2, Akshat Gupta 1 2, Renu Sharma 1 2, Huayan Ren 1 2, Rohit Bhargava 2 3, Yue Wang 1 2, Xiao-Song Wang 4 5

    Nature communications

    Lawal et al. identified an immune-privileging regulon signature (IMPREG) from tumor samples of patients who were non-responsive to ICB. IMPREG mirrors transcriptional programs of immune-privileged organs. Transcriptomics revealed that IMPREG was activated via three compartments: immature neuronal-like malignant cells, myofibroblastic CAFs, or endothelial cells, forming niches devoid of effector T cells and enriched for TGFβ3, CXCL12, and IL-34-driven suppressive circuits. High IMPREG scores predicted ICB resistance in 14 cancer types, and was associated with increased sensitivity to EGFR inhibitors and anti-angiogenic therapies.

    Contributed by Shishir Pant

    Bashir Lawal 1 2, Akshat Gupta 1 2, Renu Sharma 1 2, Huayan Ren 1 2, Rohit Bhargava 2 3, Yue Wang 1 2, Xiao-Song Wang 4 5

    Nature communications

    Lawal et al. identified an immune-privileging regulon signature (IMPREG) from tumor samples of patients who were non-responsive to ICB. IMPREG mirrors transcriptional programs of immune-privileged organs. Transcriptomics revealed that IMPREG was activated via three compartments: immature neuronal-like malignant cells, myofibroblastic CAFs, or endothelial cells, forming niches devoid of effector T cells and enriched for TGFβ3, CXCL12, and IL-34-driven suppressive circuits. High IMPREG scores predicted ICB resistance in 14 cancer types, and was associated with increased sensitivity to EGFR inhibitors and anti-angiogenic therapies.

    Contributed by Shishir Pant

    ABSTRACT: Immune checkpoint blockade (ICB) has transformed oncology, yet most patients fail to respond, suffer from hyper-progressive disease, or face severe immune-related toxicities, underscoring the urgent need for biomarkers that identify non-responders. Here we show that tumors co-opt an immune-privileging regulon signature (IMPREG) mirroring transcriptional programs of immune-privileged organs - to enforce T-cell desertion and ICB resistance across solid tumor types. Single-cell and spatial transcriptomic analyses reveal that tumors activate IMPREG through three distinct cellular routes: malignant cells adopting immature neuronal states, cancer-associated fibroblasts assuming myofibroblast identities, or endothelial cells - each creating localized niches of immune suppression and antigen-presentation collapse. Across 4 discovery and 36 validation clinical datasets, IMPREG consistently predicts immunotherapy resistance in 14 distinct cancer types, functioning as an orthogonal marker independent of established biomarkers. Crucially, IMPREG-expressing tumors show enhanced sensitivity to EGFR inhibitors or anti-angiogenic therapies in specific tumor entities. These findings suggest IMPREG as a dual-utility predictive biomarker for personalized treatment stratification.

    Author Info: 1UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. 2Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. 3Magee-Womens Hospital of UPMC,

    Author Info: 1UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. 2Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. 3Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA. 4UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. xiaosongw@pitt.edu. 5Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA. xiaosongw@pitt.edu.

    Citation: Nat Commun 2026 May 8 Epub05/08/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42103714

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      CD39+CD49a+CD103+ cytotoxic tissue-resident natural killer cells infiltrate and control solid epithelial tumor growth in mice

      Featured  

      Nina B Horowitz 1 2, Imran A Mohammad 1, June Ho Shin 1, John W Hickey 3 4, Peter Chockley 5 6, Gail Snyder 1, Chen Chen 1, Keene Lee 1, Krishna Sharma 1, Quan Tran 1, Anahita Nejatfard 7, Sainiteesh Maddineni 1, Vasu Divi 1, Catherine A Blish 8, Garry P Nolan 4, Jennifer A Foltz 9 10, John B Sunwoo 1

      Science translational medicine

      Two recent papers phenotyped tumoral NK cell subsets. Lozada et al. detected a tissue-resident (TR) adaptive subset that was IFNG-driven, associated with better clinical outcomes and response to checkpoint blockade, while canonical NK cells expressed high TGFB1 and were suppressive. Horowitz, Mahammad, Ho Shin et al. also found that tissue-resident CD49a+CD103+ NK cells (trNK cells) can have suppressive or cytotoxic functions. A cytotoxic trNK population expressing CD39 had the highest cytolytic antitumor activity and could be differentiated and expanded ex vivo for adoptive transfer.

      Nina B Horowitz 1 2, Imran A Mohammad 1, June Ho Shin 1, John W Hickey 3 4, Peter Chockley 5 6, Gail Snyder 1, Chen Chen 1, Keene Lee 1, Krishna Sharma 1, Quan Tran 1, Anahita Nejatfard 7, Sainiteesh Maddineni 1, Vasu Divi 1, Catherine A Blish 8, Garry P Nolan 4, Jennifer A Foltz 9 10, John B Sunwoo 1

      Science translational medicine

      Two recent papers phenotyped tumoral NK cell subsets. Lozada et al. detected a tissue-resident (TR) adaptive subset that was IFNG-driven, associated with better clinical outcomes and response to checkpoint blockade, while canonical NK cells expressed high TGFB1 and were suppressive. Horowitz, Mahammad, Ho Shin et al. also found that tissue-resident CD49a+CD103+ NK cells (trNK cells) can have suppressive or cytotoxic functions. A cytotoxic trNK population expressing CD39 had the highest cytolytic antitumor activity and could be differentiated and expanded ex vivo for adoptive transfer.

      ABSTRACT: Human tissue-resident natural killer (NK) cells (trNK cells), broadly defined by markers of tissue residency, such as CD49a [integrin α1 (ITGA1)] and CD103 [integrin αE (ITGAE)], are increasingly recognized for their immunoregulatory role in host control of infection, malignancy, and autoimmunity. Although the importance of transforming growth factor-β in trNK cell differentiation has been demonstrated, the context in which the differentiation of CD49a+CD103+ trNK cells occurs can result in either an immunosuppressive phenotype (e.g., decidual NK cells) or a highly cytotoxic one (e.g., some tumor trNK subsets). To understand this dichotomy better, we used a multiomic approach to molecularly characterize these cells. We identified a cytotoxic trNK (ctrNK) cell population, characterized by the expression of CD39. These ctrNK cells exhibited superior cytolytic activity against tumor target cells, enhanced capacity to infiltrate into solid tumor microenvironments, and augmented ability to control solid tumor growth in vivo compared with conventionally activated peripheral NK cells. This heightened cytolytic and infiltrative functionality of ctrNK cells appeared to be conferred, in part, by the expression of CD103 and by avidity for tumor targets. Because adoptive immune cell therapy of solid tumor malignancies has been challenged by the inefficiency of ex vivo expanded immune cells to infiltrate immunosuppressive solid tumor microenvironments, our observations that ctrNK cells can be differentiated and expanded ex vivo present a potential platform for adoptive cell therapy of solid tumor malignancies.

      Author Info: 1Department of Otolaryngology-Head & Neck Surgery, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. 2Department of Bioengineering, Stanfo

      Author Info: 1Department of Otolaryngology-Head & Neck Surgery, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. 2Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. 3Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. 4Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. 5Pelotonia Institute for Immuno-Oncology, Ohio State University Comprehensive Cancer Center-the James, Columbus, OH 43210, USA. 6Department of Molecular Medicine and Therapeutics, College of Medicine, Ohio State University, Columbus, OH 43210, USA. 7Department of Biochemistry, Stanford University, Stanford, CA 94305, USA. 8Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. 9Section of Computational Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. 10Siteman Cancer Center at WashU Medicine, St. Louis, MO 63110, USA.

      Citation: Sci Transl Med 2026 May 6 18:eadw5567 Epub05/06/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42090477

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        Integrated Single-Cell Profiling Reveals Dichotomous NK Cell Populations Associated with Immunosuppression in Solid Tumors Featured  

        John R Lozada 1, Atef Ali 1, Christine Luo 1, Rosemary N Plagens 2, Bin Zhang 3, Andrew Elliott 4, Ella Boytim 5, Nicholas A Zorko 6, Elisabeth I Heath 7, Akash Patnaik 8, Ari M VanderWalde 9, Emmanuel S Antonarakis 1, Jeffrey S Miller 10, Justin H Hwang 10, Frank Cichocki 1

        Cancer immunology research | Free PMC Article

        Two recent papers phenotyped tumoral NK cell subsets. Lozada et al. detected a tissue-resident (TR) adaptive subset that was IFNG-driven, associated with better clinical outcomes and response to checkpoint blockade, while canonical NK cells expressed high TGFB1 and were suppressive. Horowitz, Mahammad, Ho Shin et al. also found that tissue-resident CD49a+CD103+ NK cells (trNK cells) can have suppressive or cytotoxic functions. A cytotoxic trNK population expressing CD39 had the highest cytolytic antitumor activity and could be differentiated and expanded ex vivo for adoptive transfer.

        John R Lozada 1, Atef Ali 1, Christine Luo 1, Rosemary N Plagens 2, Bin Zhang 3, Andrew Elliott 4, Ella Boytim 5, Nicholas A Zorko 6, Elisabeth I Heath 7, Akash Patnaik 8, Ari M VanderWalde 9, Emmanuel S Antonarakis 1, Jeffrey S Miller 10, Justin H Hwang 10, Frank Cichocki 1

        Cancer immunology research | Free PMC Article

        Two recent papers phenotyped tumoral NK cell subsets. Lozada et al. detected a tissue-resident (TR) adaptive subset that was IFNG-driven, associated with better clinical outcomes and response to checkpoint blockade, while canonical NK cells expressed high TGFB1 and were suppressive. Horowitz, Mahammad, Ho Shin et al. also found that tissue-resident CD49a+CD103+ NK cells (trNK cells) can have suppressive or cytotoxic functions. A cytotoxic trNK population expressing CD39 had the highest cytolytic antitumor activity and could be differentiated and expanded ex vivo for adoptive transfer.

        ABSTRACT: Natural killer (NK) cells represent key effectors of antitumor immunity, yet emerging evidence highlights populations with distinct roles in cancer. Despite such expanded diversity within the NK cell repertoire, we lack an understanding of how this heterogeneity impacts immune responses and downstream clinical outcomes. Using single-cell RNA-sequencing (scRNA-seq), we systematically profiled NK cells across cancer and uncovered a dichotomous phenotypic and functional landscape of tumor-infiltrating NK cells shaped by opposing intrinsic signaling programs that drive the expression of IFNG or TGFB1. These divergent programs are associated with distinct transcription factor circuits that integrate cues within the tumor microenvironment and skew NK cells towards pro-inflammatory or suppressive functions. We found that the capacity for NK cells to engage in either functional direction is intrinsically linked to their phenotypic identity. Canonical NK cells recruited from circulation predominantly directed suppressive TGFB1 signals towards effector CD8+ T cells in tumors. Of note, these subsets exhibited higher TGFB1 expression than intratumoral myeloid cells across tumor types. In contrast, a tissue-resident adaptive subset exhibited exclusively pro-inflammatory IFNG-driven profiles and was associated with prolonged survival in both primary and metastatic tumor settings. Moreover, these tissue-resident adaptive NK cells, but not other subsets, were linked to response to immune checkpoint blockade. Collectively, our study reveals a previously unrecognized regulatory axis in NK cells that shapes NK cell diversity and augments broader antitumor immune responses.

        Author Info: 1University of Minnesota Minneapolis United States. 2Caris Life Sciences (United States) Irving, Texas United States. 3University of Minnesota Cancer Center Minneapolis United Stat

        Author Info: 1University of Minnesota Minneapolis United States. 2Caris Life Sciences (United States) Irving, Texas United States. 3University of Minnesota Cancer Center Minneapolis United States. 4Caris Life Sciences (United States) Phoenix, AZ United States. 5University of Minnesota Minnesota, MN United States. 6University of Minnesota Minneapolis, Minnesota United States. 7Mayo Clinic Rochester, MN United States. 8University of Chicago Chicago, IL United States. 9Caris Life Sciences (United States) Los Angeles, CA United States. 10University of Minnesota Minneapolis, MN United States.

        Citation: Cancer Immunol Res 2026 Feb 27 Epub02/27/2026

        Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41758966

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          Polymer-mRNA complexes for monocyte-trafficked, lymph node-targeted cancer vaccination Spotlight 

          Qiongzhe Ren # 1, Xiaofei Zhao # 1, Lili Zhou # 2, Ruonan Ye 1, Liguo Chen 1, Keyun Ren 3, Xijun Piao 3, Yihan Zhou 4, Yiming Qi 5, Kevin C Chan 4, Li Cao 6, Liang Du 7, Peng Gao 7, Bo Ying 7, Chao Deng 1, Fenghua Meng 1, Fangfang Zhou 8, Congcong Xu 9 10 11, Zhiyuan Zhong 12 13 14

          Nature biomedical engineering

          To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.

          Contributed by Lauren Hitchings

          Qiongzhe Ren # 1, Xiaofei Zhao # 1, Lili Zhou # 2, Ruonan Ye 1, Liguo Chen 1, Keyun Ren 3, Xijun Piao 3, Yihan Zhou 4, Yiming Qi 5, Kevin C Chan 4, Li Cao 6, Liang Du 7, Peng Gao 7, Bo Ying 7, Chao Deng 1, Fenghua Meng 1, Fangfang Zhou 8, Congcong Xu 9 10 11, Zhiyuan Zhong 12 13 14

          Nature biomedical engineering

          To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.

          Contributed by Lauren Hitchings

          ABSTRACT: Lymph nodes are the primary sites where adaptive immunity is initiated, yet most messenger RNA cancer vaccines reach them inefficiently and instead accumulate in organs such as the liver, limiting therapeutic potency and increasing systemic toxicity. Here we developed a transferrin receptor-associating polyplex formed by electrostatic complexation of mRNA with low-molecular-weight polyethylenimine that had been chemically modified with cyclic disulfide monomers to enhance nucleic acid binding stability, enable thiol-based transferrin receptor engagement and reduce off-target liver uptake. After subcutaneous administration, these polyplexes activated innate immunity, rapidly recruited monocytes with high transferrin receptor expression and bound these cells through cyclic disulfide-mediated interactions. Monocytes then trafficked the vaccine to draining lymph nodes, where mRNA translation and antigen presentation occurred. Delivery of ovalbumin and interleukin 12 mRNA elicited strong antigen-specific cytotoxic T cell responses and inhibited melanoma progression and metastatic disease. Studies using Survivin and human papillomavirus antigens in distinct tumour models demonstrated broad applicability. This monocyte-driven lymph node-targeting strategy enables potent and selective delivery of mRNA cancer vaccines.

          Author Info: 1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. 2Institutes of Biology and Medical Scien

          Author Info: 1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. 2Institutes of Biology and Medical Science, Soochow University, Suzhou, P. R. China. 3Catug Biotechnology Co. Ltd, Suzhou, P. R. China. 4Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, P. R. China. 5School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China. 6College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. 7Suzhou Abogen Biosciences Co. Ltd, Suzhou, P. R. China. 8Institutes of Biology and Medical Science, Soochow University, Suzhou, P. R. China. zhoufangfang@suda.edu.cn. 9Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 10College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 11International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 12Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. 13College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. 14International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. #Contributed equally.

          Citation: Nat Biomed Eng 2026 May 5 Epub05/05/2026

          Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42086923

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            Ferroptosis-armed dendritic cell vaccines for glioma immunotherapy Spotlight 

            Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2

            Nature communications

            A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.

            Contributed by Alex Najibi

            Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2

            Nature communications

            A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.

            Contributed by Alex Najibi

            ABSTRACT: The type of cell death has proven to play a crucial role in cancer immunotherapy efficacy. Immunogenic cell death (ICD) enhances tumor adjuvanticity and antigenicity by releasing danger signals and altering the immune peptidome. The immunogenicity of ferroptosis, an iron-dependent form of cell death, remains uncertain. Here, we show that dendritic cell (DC) vaccines loaded with ferroptotic lysates protect mice against glioma growth, inducing IFN-_ production, and promoting robust CD8_ T cell infiltration, activation, and effector memory formation in the tumor microenvironment. The intrinsic immunogenicity of ferroptosis was independent of the glioma type and the ferroptosis inducer. Instead, it critically required the presence of the damage-associated molecular patterns calreticulin and ATP, rather than involving HMGB1-TLR4 signaling. However, supplementing these DAMPs into DC vaccines loaded with non-ICD lysates did not restore efficacy to the level of the ferroptosis-based DC vaccine, suggesting a more complex mechanism beyond a purely DAMP-mediated effect. These findings demonstrate that ferroptosis-loaded DC vaccines elicit a potent, tumor-specific immune response, capable of eradicating intracranial gliomas in mice, which highlights their potential in cancer immunotherapy.

            Author Info: 1Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent Unive

            Author Info: 1Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 2Cancer Research Institute Ghent, Ghent, Belgium. 3Institute of Neurosciences, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia. 4Thoracic Tumor Immunology Laboratory (TTIL), Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Science, Ghent University, Ghent, Belgium. 5VIB Proteomics Core, VIB, Ghent, Belgium. 6VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium. 7Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 8myNEO Therapeutics, Ghent, Belgium. 9IBiTech-MEDISIP-Infinity Laboratory, Department of Electronics and Information Systems, Faculty of Engineering and Architecture, Ghent University, Ghent, Belgium. 10Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 11Neurology Clinic, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany. 12Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France. 13Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 144Brain, Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 15Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia. 16VIB Center for Inflammation Research, Ghent, Belgium. 17Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium. 18Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. elena.catanzaro@ugent.be. 19Cancer Research Institute Ghent, Ghent, Belgium. elena.catanzaro@ugent.be. #Contributed equally.

            Citation: Nat Commun 2026 May 7 Epub05/07/2026

            Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42098128

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              Intermetallic nanoassemblies potentiate systemic STING activation Spotlight 

              Xingwu Zhou # 1 2, Xiang Ling # 1 2, Xiaoqi Sun 1 2, Ziye Wan 1 2, Tobias Dwyer 3, Timothy C Moore 3, Quguang Li 1 2, Hannah E Dobson 1 2, Qi Wu 1 2, Xiangbo Kong 4, Fang Xie 1 2, Xinran An 1 2, Jingyao Gan 1 2, Kaikai Wang 1 2, Young Seok Cho 1 2, Wang Gong 5, Katherine Dong 1 2, Jie Zhang 1 2, Mariko Takahashi 1 2, Cheng Xu 1 2, Swetha Kodamasimham 1 2, Jie Xu 4, Vilma Yuzbasiyan-Gurkan 6 7, Steven B Chinn 8, Anna Schwendeman 1 2, Sharon C Glotzer 2 3, Yu Leo Lei 5, James J Moon 1 2 3 9 10

              Science

              Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.

              Contributed by Shishir Pant

              Xingwu Zhou # 1 2, Xiang Ling # 1 2, Xiaoqi Sun 1 2, Ziye Wan 1 2, Tobias Dwyer 3, Timothy C Moore 3, Quguang Li 1 2, Hannah E Dobson 1 2, Qi Wu 1 2, Xiangbo Kong 4, Fang Xie 1 2, Xinran An 1 2, Jingyao Gan 1 2, Kaikai Wang 1 2, Young Seok Cho 1 2, Wang Gong 5, Katherine Dong 1 2, Jie Zhang 1 2, Mariko Takahashi 1 2, Cheng Xu 1 2, Swetha Kodamasimham 1 2, Jie Xu 4, Vilma Yuzbasiyan-Gurkan 6 7, Steven B Chinn 8, Anna Schwendeman 1 2, Sharon C Glotzer 2 3, Yu Leo Lei 5, James J Moon 1 2 3 9 10

              Science

              Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.

              Contributed by Shishir Pant

              ABSTRACT: Natural systems use metal ions to form ordered structures that regulate biological processes, inspiring the rational design of nanotherapeutics. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway drives antitumor immunity but has been difficult to activate systemically owing to poor pharmacology and toxicity. Here, we report CRYSTAL, a structurally ordered intermetallic nanoparticle for potent systemic STING activation. CRYSTAL self-assembles from manganese ions intercalated with cyclic dinucleotides, enabling precise structural control. At an ultralow intravenous dose (0.003 milligrams per kilogram), CRYSTAL activated STING in mice, dogs, and nonhuman primates without cytokine release syndrome. CRYSTAL induced robust tumor regression in advanced murine and rabbit models, remodeled immunosuppressive environments, and promoted host STING-dependent CD8(+) T cell priming. CRYSTAL activated interferon responses in human head and neck squamous cell carcinoma biopsies, underscoring its translational potential for cancer immunotherapy.

              Author Info: 1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. 2Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. 3Department of Chemical En

              Author Info: 1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. 2Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. 3Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. 4Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA. 5Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA. 7Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA. 8Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA. 9Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. 10Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. #Contributed equally.

              Citation: Science 2026 May 7 392:eadx1893 Epub05/07/2026

              Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42096576

              Tags:

                mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression Spotlight 

                (1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

                Nature biotechnology

                To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

                Contributed by Ute Burkhardt

                (1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

                Nature biotechnology

                To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

                Contributed by Ute Burkhardt

                ABSTRACT: Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

                Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

                Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

                Citation: Nat Biotechnol 2026 Apr 29 Epub04/29/2026

                Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056385

                Tags:

                Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality

                Spotlight 

                (1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

                Science

                Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

                Contributed by Paula Hochman

                (1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

                Science

                Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

                Contributed by Paula Hochman

                ABSTRACT: The generation of effector CD8(+) T cells (T(EFF)) requires activation of nave CCR7(+) T cells (T(N)) by dendritic cells (DCs) in lymphoid tissue. How T(N)-DC interaction duration and signal integration are controlled remains unclear. In this study, we show that lymphoid stroma-secreted CCR7 ligands limit interaction duration by progressively inducing CD8(+) T cell release from DCs. At late interaction stages, CCR7 ligands relocalize the F-actin regulator DOCK2 away from the DC interface, permitting T cell detachment, proliferation onset, and acquisition of cytotoxicity. Disruption of CCR7 signaling causes prolonged T cell-DC contacts and produces dysfunctional T(EFF) with elevated inhibitory receptors, reduced antimicrobial activity, and impaired recall responses. Stromal chemokines therefore act as critical regulators of T cell priming by DCs, preserving CD8(+) effector function during acute and memory phases.

                Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribo

                Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (3) Department of Biomedicine, University of Basel, Basel, Switzerland. (4) Department of Biology, University of Fribourg, Fribourg, Switzerland. (5) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (7) Institute of Neuropathology, UniversitŠtsklinikum Erlangen, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (8) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (9) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (10) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (11) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (12) Department of Biomedicine, University of Basel, Basel, Switzerland. (13) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (14) Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland. Department of Urology, Inselspital University Hospital, Bern, Switzerland. Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Department of Surgery, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. (15) Department of Biology, University of Fribourg, Fribourg, Switzerland. (16) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (17) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland.

                Citation: Science 2026 Apr 30 392:eadq2080 Epub04/30/2026

                Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42060746

                Tags:

                Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1 Featured  

                (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

                Nature

                Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

                (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

                Nature

                Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

                ABSTRACT: Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer(1). Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1_mg_kg(-1)) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3_mg_kg(-1)) or intravenous ipilimumab (3_mg_kg(-1)). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (T(reg)) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural T(reg) cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fc_ receptor (Fc_R) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated T(reg) cell and Fc_R(+) M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

                Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie I

                Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (2) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (3) Gustave Roussy, Service de Biostatistiques et d'EpidŽmiologie (SBE), UniversitŽ Paris Saclay, Villejuif, France. INSERM U1018, ONCOSTAT, Equipe LabellisŽe Ligue contre le Cancer, Villejuif, France. (4) INSERM U981, Gustave Roussy, Villejuif, France. (5) Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (6) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. (7) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (8) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (9) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (10) Gustave Roussy, DŽpartement d'Imagerie MŽdicale, Villejuif, France. (11) Gustave Roussy, Service de Promotion d'Etudes Cliniques, DRC, Villejuif, France. (12) INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (13) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (14) INSERM CIC 1428, BIOTHERIS, Villejuif, France. (15) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (16) Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (17) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (18) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (19) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U1015, Immunologie des tumeurs et immunothŽrapie contre le cancer, Villejuif, France. (20) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (21) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, Service de Pharmacologie, DŽpartement de Biologie et Pathologie mŽdicales, Villejuif, France. (22) INSERM CIC 1428, BIOTHERIS, Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (23) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (24) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (25) INSERM U981, Gustave Roussy, Villejuif, France. (26) CHU de Toulouse, Service d'Oncodermatologie, IUCT-O, Toulouse, France. INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France. UniversitŽ Toulouse III - Paul Sabatier, DŽpartement de Dermatologie, Toulouse, France. (27) UniversitŽ Paris CitŽ, AP-HP Dermato-oncologie et CIC, Institut du Cancer APHP nord, Paris, France. INSERM U1342-Equipe 1-CNRS EMR8000, H™pital Saint Louis, Paris, France. (28) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. INSERM U1052-CNRS UMR5286, PlasticitŽ Tumorale dans le MŽlanome, Centre de Recherche en CancŽrologie de Lyon, Centre LŽon BŽrard, Lyon, France. UniversitŽ Claude Bernard Lyon 1, Lyon, France. (29) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (30) INSERM CIC 1428, BIOTHERIS, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. aurelien.marabelle@gustaveroussy.fr. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. aurelien.marabelle@gustaveroussy.fr.

                Citation: Nature 2026 Apr 29 Epub04/29/2026

                Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056527

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