Journal Articles

Coupling IL-2 with IL-10 to mitigate toxicity and enhance antitumor immunity Spotlight 

(1) Ahn JJ (2) Dudics S (3) Langan DP (4) Smith JD (5) Hsu AH (6) McCright JC (7) Smith SR (8) Castleberry AL (9) George BI (10) Goitía Vázquez JA (11) Kuri PN (12) Alla SSV (13) Garcia J (14) Haider YM (15) Hamdan FW (16) Juárez JE (17) Reddy R (18) Shanmuganathan A (19) Wang Y (20) Welch A (21) Boclair D (22) Khrimian PA (23) Yaen CH (24) Mumm JB

Cell reports. Medicine

Ahn et al. showed in vitro (using human PBMCs) and in mice that IL-10 suppressed IL-2 induction of CRS-associated cytokines by suppressing TNFα production while potentiating IL-2-mediated antitumor activities. DK210(EGFR) – a fusion protein comprising IL-2 coupled to a high-affinity IL-10 mutein targeted by an anti-EGFR scFv scaffold to tumor cells – activated CTLs and NK cells, increased perforin/granzyme B secretion, limited Treg expansion, boosted the CD8+ T cell/Treg ratio within tumors, sustained CTL functions, and enhanced efficacy in murine tumor models. In NHP, at projected therapeutic doses, DK210(EGFR) induced immune activation without inducing CRS or significant organ toxicity.

Contributed by Paula Hochman

(1) Ahn JJ (2) Dudics S (3) Langan DP (4) Smith JD (5) Hsu AH (6) McCright JC (7) Smith SR (8) Castleberry AL (9) George BI (10) Goitía Vázquez JA (11) Kuri PN (12) Alla SSV (13) Garcia J (14) Haider YM (15) Hamdan FW (16) Juárez JE (17) Reddy R (18) Shanmuganathan A (19) Wang Y (20) Welch A (21) Boclair D (22) Khrimian PA (23) Yaen CH (24) Mumm JB

Cell reports. Medicine

Ahn et al. showed in vitro (using human PBMCs) and in mice that IL-10 suppressed IL-2 induction of CRS-associated cytokines by suppressing TNFα production while potentiating IL-2-mediated antitumor activities. DK210(EGFR) – a fusion protein comprising IL-2 coupled to a high-affinity IL-10 mutein targeted by an anti-EGFR scFv scaffold to tumor cells – activated CTLs and NK cells, increased perforin/granzyme B secretion, limited Treg expansion, boosted the CD8+ T cell/Treg ratio within tumors, sustained CTL functions, and enhanced efficacy in murine tumor models. In NHP, at projected therapeutic doses, DK210(EGFR) induced immune activation without inducing CRS or significant organ toxicity.

Contributed by Paula Hochman

ABSTRACT: Wild-type interleukin (IL)-2 induces anti-tumor immunity and toxicity, predominated by vascular leak syndrome (VLS) leading to edema, hypotension, organ toxicity, and regulatory T cell (Treg) expansion. Efforts to uncouple IL-2 toxicity from its potency have failed in the clinic. We hypothesize that IL-2 toxicity is driven by cytokine release syndrome (CRS) followed by VLS and that coupling IL-2 with IL-10 will ameliorate toxicity. Our data, generated using human primary cells, mouse models, and non-human primates, suggest that coupling of these cytokines prevents toxicity while retaining cytotoxic T cell activation and limiting Treg expansion. In syngeneic murine tumor models, DK210 epidermal growth factor receptor (EGFR), an IL-2/IL-10 fusion molecule targeted to EGFR via an anti-EGFR single-chain variable fragment (scFV), potently activates T cells and natural killer (NK) cells and elicits interferon (IFN)γ-dependent anti-tumor function without peripheral inflammatory toxicity or Treg accumulation. Therefore, combining IL-2 with IL-10 uncouples toxicity from immune activation, leading to a balanced and pleiotropic anti-tumor immune response.

Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germa

Author Info: (1) Deka Biosciences, Inc., Germantown, MD, USA. (2) Deka Biosciences, Inc., Germantown, MD, USA. (3) Deka Biosciences, Inc., Germantown, MD, USA. (4) Deka Biosciences, Inc., Germantown, MD, USA. (5) Deka Biosciences, Inc., Germantown, MD, USA. (6) Deka Biosciences, Inc., Germantown, MD, USA. (7) Deka Biosciences, Inc., Germantown, MD, USA. (8) Deka Biosciences, Inc., Germantown, MD, USA. (9) Deka Biosciences, Inc., Germantown, MD, USA. (10) Deka Biosciences, Inc., Germantown, MD, USA. (11) Deka Biosciences, Inc., Germantown, MD, USA. (12) Deka Biosciences, Inc., Germantown, MD, USA. (13) Deka Biosciences, Inc., Germantown, MD, USA. (14) Deka Biosciences, Inc., Germantown, MD, USA. (15) Deka Biosciences, Inc., Germantown, MD, USA. (16) Deka Biosciences, Inc., Germantown, MD, USA. (17) Deka Biosciences, Inc., Germantown, MD, USA. (18) Deka Biosciences, Inc., Germantown, MD, USA. (19) Deka Biosciences, Inc., Germantown, MD, USA. (20) Deka Biosciences, Inc., Germantown, MD, USA. (21) Deka Biosciences, Inc., Germantown, MD, USA. (22) Deka Biosciences, Inc., Germantown, MD, USA. (23) Deka Biosciences, Inc., Germantown, MD, USA. (24) Deka Biosciences, Inc., Germantown, MD, USA. Electronic address: mummj@dekabiosciences.com.

Citation: Cell Rep Med 2025 Jul 24 102257 Epub07/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40744022

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Cancer immunology data engine reveals secreted AOAH as a potential immunotherapy Spotlight 

(1) Gong L (2) Luo J (3) Yang E (4) Ru B (5) Qi Z (6) Yang Y (7) Rani A (8) Purohit A (9) Zhang Y (10) Guan G (11) Paul R (12) Vu T (13) Chen Z (14) Ji R (15) Day CP (16) Wu C (17) Merlino G (18) Fitzgerald D (19) Altan-Bonnet G (20) Aldape K (21) Wu J (22) Guan X (23) Jiang P

Cell

Gong and Luo et al. developed the Cancer Immunology Data Engine (CIDE) using 90 omics datasets with 8,575 profiles from 5,957 patients with 17 solid tumor types. They identified acyloxyacyl hydrolase (AOAH) as a secreted protein that enhances TCR activation and DC function by depleting immunosuppressive arachidonoyl phosphatidylcholines. AOAH overexpression, even in 10% of tumor cells, or intratumoral treatment with recombinant AOAH, boosted the efficacy of immune checkpoint blockade (ICB) and tumor infiltration with CD8+ T cells and CD11c+ DCs in mouse models. AOAH expression was higher in patients responding to ICB.

Contributed by Ute Burkhardt

(1) Gong L (2) Luo J (3) Yang E (4) Ru B (5) Qi Z (6) Yang Y (7) Rani A (8) Purohit A (9) Zhang Y (10) Guan G (11) Paul R (12) Vu T (13) Chen Z (14) Ji R (15) Day CP (16) Wu C (17) Merlino G (18) Fitzgerald D (19) Altan-Bonnet G (20) Aldape K (21) Wu J (22) Guan X (23) Jiang P

Cell

Gong and Luo et al. developed the Cancer Immunology Data Engine (CIDE) using 90 omics datasets with 8,575 profiles from 5,957 patients with 17 solid tumor types. They identified acyloxyacyl hydrolase (AOAH) as a secreted protein that enhances TCR activation and DC function by depleting immunosuppressive arachidonoyl phosphatidylcholines. AOAH overexpression, even in 10% of tumor cells, or intratumoral treatment with recombinant AOAH, boosted the efficacy of immune checkpoint blockade (ICB) and tumor infiltration with CD8+ T cells and CD11c+ DCs in mouse models. AOAH expression was higher in patients responding to ICB.

Contributed by Ute Burkhardt

ABSTRACT: Secreted proteins are central mediators of intercellular communications and can serve as therapeutic targets in diverse diseases. The ∼1,903 human genes encoding secreted proteins are difficult to study through common genetic approaches. To address this hurdle and, more generally, to discover cancer therapeutics, we developed the Cancer Immunology Data Engine (CIDE, https://cide.ccr.cancer.gov), which incorporates 90 omics datasets spanning 8,575 tumor profiles with immunotherapy outcomes from 17 solid tumor types. CIDE systematically identifies all genes associated with immunotherapy outcomes. Then, we focused on secreted proteins prioritized by CIDE without known cancer roles and validated regulatory effects on immune checkpoint blockade for AOAH, CR1L, COLQ, and ADAMTS7 in mouse models. The top hit, acyloxyacyl hydrolase (AOAH), potentiates immunotherapies in multiple tumor models by sensitizing T cell receptors to weak antigens and protecting dendritic cells through depleting immunosuppressive arachidonoyl phosphatidylcholines and oxidized derivatives.

Author Info: (1) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Department of Clin

Author Info: (1) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (2) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (3) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (4) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (5) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (6) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. (7) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (8) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (9) State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China. (10) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (11) Office of the Director, CCR, NCI, NIH, Bethesda, MD 20892, USA. (12) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (13) Experimental Immunology Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (14) School of Public Health, HKU, Hong Kong, China. (15) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. (16) Experimental Immunology Branch, CCR, NCI, NIH, Bethesda, MD 20892, USA. (17) Laboratory of Cancer Biology and Genetics, CCR, NCI, NIH, Bethesda, MD 20892, USA. (18) Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (19) Laboratory of Integrative Cancer Immunology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (20) Laboratory of Pathology, CCR, NCI, NIH, Bethesda, MD 20892, USA. (21) WuXi Biologics, 7 Clark Drive, Cranbury, NJ 08512, USA. (22) Department of Clinical Oncology, The University of Hong Kong (HKU), Hong Kong, China. Electronic address: xyguan@hku.hk. (23) Cancer Data Science Lab, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: peng.jiang@nih.gov.

Citation: Cell 2025 Jul 24 Epub07/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40730154

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Microbiota-driven antitumour immunity mediated by dendritic cell migration Spotlight 

(1) Lin NY (2) Fukuoka S (3) Koyama S (4) Motooka D (5) Tourlousse DM (6) Shigeno Y (7) Matsumoto Y (8) Yamano H (9) Murotomi K (10) Tamaki H (11) Irie T (12) Sugiyama E (13) Kumagai S (14) Itahashi K (15) Tanegashima T (16) Fujimaki K (17) Ito S (18) Shindo M (19) Tsuji T (20) Wake H (21) Watanabe K (22) Maeda Y (23) Enokida T (24) Tahara M (25) Yamashita R (26) Fujisawa T (27) Nomura M (28) Kawazoe A (29) Goto K (30) Doi T (31) Shitara K (32) Mano H (33) Sekiguchi Y (34) Nakamura S (35) Benno Y (36) Nishikawa H

Nature

Lin, Fukuoka, and Koyama et al. focused on how gut microbiota influence the clinical efficacy of ICB. A newly identified bacterial strain named YB328 (genus hominenteromicrobium), was significantly elevated in feces of patients who responded to PD-1 inhibition. Mechanistically, YB328 promoted antitumor efficacy by activating tumor-specific CD103+CD11b- conventional DCs in the gut via multiple TLRs, promoting their migration and in situ activation of a broader repertoire of PD1+CD8+ T cells in the dLNs and TME. YB328 enhanced ICB efficacy in multiple tumor models, and levels correlated with PFS in various cancer types.

Contributed by Katherine Turner

(1) Lin NY (2) Fukuoka S (3) Koyama S (4) Motooka D (5) Tourlousse DM (6) Shigeno Y (7) Matsumoto Y (8) Yamano H (9) Murotomi K (10) Tamaki H (11) Irie T (12) Sugiyama E (13) Kumagai S (14) Itahashi K (15) Tanegashima T (16) Fujimaki K (17) Ito S (18) Shindo M (19) Tsuji T (20) Wake H (21) Watanabe K (22) Maeda Y (23) Enokida T (24) Tahara M (25) Yamashita R (26) Fujisawa T (27) Nomura M (28) Kawazoe A (29) Goto K (30) Doi T (31) Shitara K (32) Mano H (33) Sekiguchi Y (34) Nakamura S (35) Benno Y (36) Nishikawa H

Nature

Lin, Fukuoka, and Koyama et al. focused on how gut microbiota influence the clinical efficacy of ICB. A newly identified bacterial strain named YB328 (genus hominenteromicrobium), was significantly elevated in feces of patients who responded to PD-1 inhibition. Mechanistically, YB328 promoted antitumor efficacy by activating tumor-specific CD103+CD11b- conventional DCs in the gut via multiple TLRs, promoting their migration and in situ activation of a broader repertoire of PD1+CD8+ T cells in the dLNs and TME. YB328 enhanced ICB efficacy in multiple tumor models, and levels correlated with PFS in various cancer types.

Contributed by Katherine Turner

ABSTRACT: Gut microbiota influence the antitumour efficacy of immune checkpoint blockade(1-6), but the mechanisms of action have not been fully elucidated. Here, we show that a new strain of the bacterial genus Hominenteromicrobium (designated YB328) isolated from the faeces of patients who responded to programmed cell death_1 (PD-1) blockade augmented antitumour responses in mice. YB328 activated tumour-specific CD8(+) T_cells through the stimulation of CD103(+)CD11b(-) conventional dendritic cells (cDCs), which, following exposure in the gut, migrated to the tumour microenvironment. Mice showed improved antitumour efficacy of PD-1 blockade when treated with faecal transplants from non-responder patients supplemented with YB238. This result suggests that YB328 could function in a dominant manner. YB328-activated CD103(+)CD11b(-) cDCs showed prolonged engagement with tumour-specific CD8(+) T_cells and promoted PD-1 expression in these cells. Moreover, YB238-augmented antitumour efficacy of PD-1 blockade treatment was observed in multiple mouse models of cancer. Patients with elevated YB328 abundance had increased infiltration of CD103(+)CD11b(-) cDCs in tumours and had a favourable response to PD-1 blockade therapy in various cancer types. We propose that gut microbiota enhance antitumour immunity by accelerating the maturation and migration of CD103(+)CD11b(-) cDCs to increase the number of CD8(+) T_cells that respond to diverse tumour antigens.

Author Info: (1) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Author Info: (1) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (2) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (3) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan. (4) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (5) Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (6) Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan. (7) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (8) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (9) Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (10) Biomanufacturing Process Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (11) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (12) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (13) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (14) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (15) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (16) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (17) Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (18) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (19) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (20) Department of Anatomy and Molecular Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan. (21) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (22) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. (23) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. (24) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. (25) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan. (26) Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Chiba, Japan. Translational Research Support Office, National Cancer Center Hospital East, Chiba, Japan. (27) Department of Head and Neck Oncology and Innovative Treatment, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (28) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (29) Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan. (30) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (31) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. (32) Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan. (33) Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, Japan. (34) Department of Infection Metagenomics, Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan. (35) Benno Laboratory, RIKEN Baton Zone Program, RIKEN Cluster for Science Technology and Innovation Laboratory, Saitama, Japan. benno828@bigm.or.jp. Benno Institute for Gut Microflora (BIGM), Saitama Industrial Technology Center, Saitama, Japan. benno828@bigm.or.jp. (36) Division of Cancer Immunology, National Cancer Center Research Institute, Tokyo, Japan. hnishika@ncc.go.jp. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan. hnishika@ncc.go.jp. Division of Cancer Immune Multicellular System Regulation, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. hnishika@ncc.go.jp. Kindai University Faculty of Medicine, Osaka, Japan. hnishika@ncc.go.jp.

Citation: Nature 2025 Jul 14 Epub07/14/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40659786

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Bispecific killer cell engager-secreting CAR-T cells redirect natural killer specificity to enhance antitumour responses Spotlight 

(1) Fan Y (2) Duan Y (3) Chen J (4) Wang Y (5) Shang K (6) Jiang J (7) Su L (8) Zhou C (9) Sadelain M (10) Huang H (11) Sun J

Nature biomedical engineering

Testing various combinations, Fan et al. found that the administration of bispecific killer cell-engager (BiKE)-secreting CAR T cells alongside weekly injections of NK cells was optimal for achieving long-term control in murine hematologic tumor models. In a solid tumor model, NK cells co-administred with BiKE+ CAR T cells showed tumor parenchyma infiltration, whereas NK cells co-administred with BiKE- CAR T cells were primarily found in the peritumoral connective tissue. The simultaneous expression of a CD19-targeting CAR and EGFR-targeting BIKEs in T cell led to complete eradication of heterogeneous EGFR+CD19- and EGFR-CD19+ tumor cells in vivo.

Contributed by Ute Burkhardt

(1) Fan Y (2) Duan Y (3) Chen J (4) Wang Y (5) Shang K (6) Jiang J (7) Su L (8) Zhou C (9) Sadelain M (10) Huang H (11) Sun J

Nature biomedical engineering

Testing various combinations, Fan et al. found that the administration of bispecific killer cell-engager (BiKE)-secreting CAR T cells alongside weekly injections of NK cells was optimal for achieving long-term control in murine hematologic tumor models. In a solid tumor model, NK cells co-administred with BiKE+ CAR T cells showed tumor parenchyma infiltration, whereas NK cells co-administred with BiKE- CAR T cells were primarily found in the peritumoral connective tissue. The simultaneous expression of a CD19-targeting CAR and EGFR-targeting BIKEs in T cell led to complete eradication of heterogeneous EGFR+CD19- and EGFR-CD19+ tumor cells in vivo.

Contributed by Ute Burkhardt

ABSTRACT: T cells and natural killer (NK) cells collaborate to maintain immune homeostasis. Current cancer immunotherapies predominantly rely on the individual application of these cells. Here we use bicistronic vectors to co-express chimeric antigen receptors (CARs) and secreted immune cell engagers (ICEs), leveraging the combined therapeutic potential of both effector cell types. After in vitro validation of immune cell engager secretion and function, various combinatorial approaches are systematically compared in mouse models, identifying a highly effective combination of bispecific killer cell engager (BiKE)-secreting CAR-T cells and NK cells. Beyond a simple combination of conventional CAR-T cells and NK cells, this strategy demonstrates superior efficacy in CD19(+) B cell leukaemia and lymphoma and EGFR(+) solid tumour models while reducing the dosage dependence on CAR-T cells. Moreover, CAR-T cells and BiKEs targeting distinct antigens exhibit suppression of tumour cells with heterogeneous antigen expression. These findings indicate that combining BiKE-secreting CAR-T cells and NK cells offers a promising strategy to combat tumour antigen heterogeneity and immune evasion.

Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Liangzhu Laboratory, Zhejiang University, Hangzhou,

Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Liangzhu Laboratory, Zhejiang University, Hangzhou, China. (2) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. (3) Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. (4) Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. (5) Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. (6) Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. (7) School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. (8) School of Public Health, Zhejiang University School of Medicine, Hangzhou, China. (9) Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, New York, NY, USA. (10) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. huanghe@zju.edu.cn. Liangzhu Laboratory, Zhejiang University, Hangzhou, China. huanghe@zju.edu.cn. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. huanghe@zju.edu.cn. (11) Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. sunj4@zju.edu.cn. Liangzhu Laboratory, Zhejiang University, Hangzhou, China. sunj4@zju.edu.cn. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China. sunj4@zju.edu.cn. Institute of Hematology, Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Zhejiang University, Hangzhou, China. sunj4@zju.edu.cn.

Citation: Nat Biomed Eng 2025 Jul 14 Epub07/14/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40659834

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Tissue origin and virus specificity shape human CD8+ T cell cytotoxicity

Spotlight 

(1) Niessl J (2) Müller TR (3) Constantz C (4) Cai C (5) Nilsén V (6) Rivera Ballesteros O (7) Adamo S (8) Kammann T (9) Mouchtaridi E (10) Gao Y (11) Akhirunnesa M (12) Raineri EJM (13) Weigel W (14) Kokkinou E (15) Stamper C (16) Marchalot A (17) Bassett J (18) Ferreira S (19) Rodahl I (20) Wild N (21) Stellaccio T (22) Brownlie D (23) Ringqvist E (24) Flodstrm-Tullberg M (25) Llewellyn-Lacey S (26) Tibbitt C (27) Hammer Q (28) Michaëlsson J (29) Price DA (30) Mjösberg J (31) Marquardt N (32) Sandberg JK (33) Sekine T (34) Jorns C (35) Buggert M

Science immunology

Niessl et al. found that blood-derived memory CD8+ T cells exhibited greater basal cytotoxic molecule expression than T cells from matched tissue, while resident memory cells exhibited the weakest cytotoxicity profile. Blood and tissue (tonsillar) effector memory CD8+ T cells also exhibited differential responses to TCR activation and cytokine stimulation (TGFβ/IL-15). Antigen specificity played a significant role in site residence and phenotype, wherein chronic virus-associated T cells exhibited greater cytotoxicity. While expression of diverse granzymes was considered a cytotoxic hallmark in blood T cells, only granzyme B was found to contribute to cell killing.

Contributed by Morgan Janes

(1) Niessl J (2) Müller TR (3) Constantz C (4) Cai C (5) Nilsén V (6) Rivera Ballesteros O (7) Adamo S (8) Kammann T (9) Mouchtaridi E (10) Gao Y (11) Akhirunnesa M (12) Raineri EJM (13) Weigel W (14) Kokkinou E (15) Stamper C (16) Marchalot A (17) Bassett J (18) Ferreira S (19) Rodahl I (20) Wild N (21) Stellaccio T (22) Brownlie D (23) Ringqvist E (24) Flodstrm-Tullberg M (25) Llewellyn-Lacey S (26) Tibbitt C (27) Hammer Q (28) Michaëlsson J (29) Price DA (30) Mjösberg J (31) Marquardt N (32) Sandberg JK (33) Sekine T (34) Jorns C (35) Buggert M

Science immunology

Niessl et al. found that blood-derived memory CD8+ T cells exhibited greater basal cytotoxic molecule expression than T cells from matched tissue, while resident memory cells exhibited the weakest cytotoxicity profile. Blood and tissue (tonsillar) effector memory CD8+ T cells also exhibited differential responses to TCR activation and cytokine stimulation (TGFβ/IL-15). Antigen specificity played a significant role in site residence and phenotype, wherein chronic virus-associated T cells exhibited greater cytotoxicity. While expression of diverse granzymes was considered a cytotoxic hallmark in blood T cells, only granzyme B was found to contribute to cell killing.

Contributed by Morgan Janes

ABSTRACT: CD8(+) T cells are classically defined by cytotoxic activity, but it has remained unclear whether cytotoxic programs are compartmentalized across tissues and memory subsets. Here, we established a human organ donor cohort and found that expression of conventional cytotoxic molecules-granulysin, perforin, and granzyme B-was most prominent among circulating memory CD8(+) T cells and decreased progressively with tissue residency, inversely mirroring the expression of CD69 and CD103. Other cytotoxic molecules, including granzymes A, H, K, and M, were variably expressed across tissues, and memory CD8(+) T cells targeting persistent viruses expressed multiple granzymes coordinately. In an in vitro tonsil system, transforming growth factor-_ induced discordant regulation of cytotoxic molecules and CD103. Combined with interleukin-15, this circuitry modulated proliferation and the acquisition of redirected killing activity via perforin and granzyme B. Our findings suggest that human memory CD8(+) T cell cytotoxicity is intricately regulated by environmental cues reflecting tissue location and antigen specificity.

Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge,

Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (3) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (4) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (5) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (6) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (7) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (8) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (9) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (10) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (11) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (12) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (13) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (14) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (15) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (16) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (17) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (18) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (19) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (20) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (21) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (22) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (23) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (24) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (25) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (26) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (27) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (28) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (29) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (30) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (31) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (32) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (33) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (34) ME Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. (35) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

Citation: Sci Immunol 2025 Jul 18 10:eadq4881 Epub07/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40680144

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Sensitization of tumours to immunotherapy by boosting early type-I interferon responses enables epitope spreading Spotlight 

(1) Qdaisat S (2) Wummer B (3) Stover BD (4) Zhang D (5) McGuiness J (6) Weidert F (7) Chardon-Robles J (8) Grippin A (9) DeVries A (10) Zhao C (11) Marconi C (12) Karachi A (13) Xie C (14) Jobin G (15) Liu R (16) Michel S (17) Ma X (18) Moor RSF (19) von Roemeling C (20) Nguyen DT (21) Elliott L (22) Thomas N (23) Barpujari A (24) Geffrard H (25) Campaneria Y (26) Ogando-Rivas E (27) Rabideau C (28) Soni D (29) Huang J (30) Carrera-Justiz S (31) Fredenburg K (32) Silver NL (33) Sawyer WG (34) Rahman M (35) Ligon JA (36) Flores CT (37) Lee JH (38) Mitchell DA (39) Castillo P (40) Mendez-Gomez HR (41) Sayour EJ

Nature biomedical engineering

Qdaisat, Wummer, and Stover et al. demonstrated that early type-I interferon responses restored a defective damage response in poorly immunogenic tumors to enable epitope spreading and sensitivity to ICB. ICB response was transferrable to resistant models due to epitope spread against poorly immunogenic tumor antigens in an IFNAR1-dependent manner. Systemic administration of lipid particles loaded with RNA coding for tumor-unspecific antigens enhanced interferon responses, induced epitope spreading, and reprogrammed the TME from myeloid suppressive to pro-inflammatory, favoring effector T cells for sustained immune response in poorly immunogenic models.

Contributed by Shishir Pant

(1) Qdaisat S (2) Wummer B (3) Stover BD (4) Zhang D (5) McGuiness J (6) Weidert F (7) Chardon-Robles J (8) Grippin A (9) DeVries A (10) Zhao C (11) Marconi C (12) Karachi A (13) Xie C (14) Jobin G (15) Liu R (16) Michel S (17) Ma X (18) Moor RSF (19) von Roemeling C (20) Nguyen DT (21) Elliott L (22) Thomas N (23) Barpujari A (24) Geffrard H (25) Campaneria Y (26) Ogando-Rivas E (27) Rabideau C (28) Soni D (29) Huang J (30) Carrera-Justiz S (31) Fredenburg K (32) Silver NL (33) Sawyer WG (34) Rahman M (35) Ligon JA (36) Flores CT (37) Lee JH (38) Mitchell DA (39) Castillo P (40) Mendez-Gomez HR (41) Sayour EJ

Nature biomedical engineering

Qdaisat, Wummer, and Stover et al. demonstrated that early type-I interferon responses restored a defective damage response in poorly immunogenic tumors to enable epitope spreading and sensitivity to ICB. ICB response was transferrable to resistant models due to epitope spread against poorly immunogenic tumor antigens in an IFNAR1-dependent manner. Systemic administration of lipid particles loaded with RNA coding for tumor-unspecific antigens enhanced interferon responses, induced epitope spreading, and reprogrammed the TME from myeloid suppressive to pro-inflammatory, favoring effector T cells for sustained immune response in poorly immunogenic models.

Contributed by Shishir Pant

ABSTRACT: The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge. Our findings show that the resistance of tumours to immunotherapy is dictated by the absence of a damage response, which can be restored by boosting early type-I interferon responses to enable epitope spreading and self-amplifying responses in treatment-refractory tumours.

Author Info: (1) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Univer

Author Info: (1) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA. (2) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (3) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (4) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (5) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (6) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (7) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (8) Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (10) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (11) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (12) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (13) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (14) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (15) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (16) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (17) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (18) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (19) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (20) Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, USA. (21) Department of Medicine, Division of Hematology and Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (22) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (23) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (24) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (25) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (26) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (27) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (28) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (29) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (30) College of Veterinary Medicine, University of Florida, Gainesville, FL, USA. (31) Department of Pathology, University of Florida, Gainesville, FL, USA. (32) Center of Immunotherapy and Precision Immuno-Oncology/Head and Neck Institute, Cleveland Clinic, Cleveland, OH, USA. (33) Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, USA. (34) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (35) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (36) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (37) Department of Biostatistics, University of Florida, Gainesville, FL, USA. (38) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (39) Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. (40) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. (41) Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. Elias.Sayour@neurosurgery.ufl.edu. Department of Pediatrics, Division of Pediatric Hematology-Oncology, UF Health Cancer Center, University of Florida, Gainesville, FL, USA. Elias.Sayour@neurosurgery.ufl.edu.

Citation: Nat Biomed Eng 2025 Jul 18 Epub07/18/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40681861

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Systemic administration of an RNA binding and cell-penetrating antibody targets therapeutic RNA to multiple mouse models of cancer Spotlight 

(1) Quijano E (2) Martinez-Saucedo D (3) Ianniello Z (4) Pinto-Medici N (5) Rackear M (6) Chen H (7) Lola-Pereira L (8) Liu Y (9) Hegan D (10) Shan X (11) Tseng R (12) Yugawa D (13) Chowdhury S (14) Khang M (15) Singh JP (16) Abdullah R (17) Azhir P (18) Kashima S (19) Woods WS (20) Gosstola N (21) Turner BC (22) Squinto S (23) Ludwig DL (24) Bindra RS (25) Robert ME (26) Braun DA (27) Perez Pinera P (28) Saltzman WM (29) Escobar-Hoyos LF (30) Glazer PM

Science translational medicine

Quijano, Martinez-Saucedo, and Ianniello et al. showed that the mAb TMAB3 noncovalently bound to 3p-hpRNA to form stable antibody/RNA complexes that delivered 3p-hpRNA specifically to premalignant and malignant cells. Intravenously administered TMAB3/ 3p-hpRNA complexes enhanced survival and suppressed tumor growth in orthotopic pancreatic cancer and medulloblastoma mouse models. Single-cell RNAseq showed that TMAB3/3p-hpRNA treatment promoted cytotoxic T cell infiltration and RIG-I activation. T cell activation mediated by TMAB3/3p-hpRNA was dependent on ENT2 and RIG-I expression on PDAC cells.

Contributed by Shishir Pant

(1) Quijano E (2) Martinez-Saucedo D (3) Ianniello Z (4) Pinto-Medici N (5) Rackear M (6) Chen H (7) Lola-Pereira L (8) Liu Y (9) Hegan D (10) Shan X (11) Tseng R (12) Yugawa D (13) Chowdhury S (14) Khang M (15) Singh JP (16) Abdullah R (17) Azhir P (18) Kashima S (19) Woods WS (20) Gosstola N (21) Turner BC (22) Squinto S (23) Ludwig DL (24) Bindra RS (25) Robert ME (26) Braun DA (27) Perez Pinera P (28) Saltzman WM (29) Escobar-Hoyos LF (30) Glazer PM

Science translational medicine

Quijano, Martinez-Saucedo, and Ianniello et al. showed that the mAb TMAB3 noncovalently bound to 3p-hpRNA to form stable antibody/RNA complexes that delivered 3p-hpRNA specifically to premalignant and malignant cells. Intravenously administered TMAB3/ 3p-hpRNA complexes enhanced survival and suppressed tumor growth in orthotopic pancreatic cancer and medulloblastoma mouse models. Single-cell RNAseq showed that TMAB3/3p-hpRNA treatment promoted cytotoxic T cell infiltration and RIG-I activation. T cell activation mediated by TMAB3/3p-hpRNA was dependent on ENT2 and RIG-I expression on PDAC cells.

Contributed by Shishir Pant

ABSTRACT: There is intense interest in the advancement of RNAs as rationally designed therapeutic agents, especially in oncology, where a major focus is to use RNAs to stimulate pattern recognition receptors to leverage innate immune responses. However, the inability to selectively deliver therapeutic RNAs within target cells after intravenous administration now hinders the development of this type of treatment for cancer and other disorders. Here, we found that a tumor-targeting, cell-penetrating, and RNA binding monoclonal antibody, TMAB3, can form stable, noncovalent antibody/RNA complexes of a discrete size that mediate highly specific and functional delivery of RNAs into tumors. Using 3p-hpRNA, an agonist of the pattern recognition receptor retinoic acid-inducible gene-I (RIG-I), we observed robust antitumor efficacy of systemically administered TMAB3/3p-hpRNA complexes in mouse models of pancreatic cancer, medulloblastoma, and melanoma. In the KPC syngeneic, orthotopic pancreatic cancer model in immunocompetent mice, treatment with TMAB3/3p-hpRNA tripled animal survival, decreased tumor growth, and specifically targeted malignant cells, with a 1500-fold difference in RNA delivery into tumor cells versus nonmalignant cells within the tumor mass. Single-cell RNA sequencing (scRNA-seq) and flow cytometry demonstrated that TMAB3/3p-hpRNA treatment elicited a potent antitumoral immune response characterized by RIG-I activation and increased infiltration and activity of cytotoxic T cells. These studies established that TMAB3/RNA complexes can deliver RNA payloads specifically to hard-to-treat tumor cells to achieve antitumor efficacy, providing an antibody-based platform to advance the study of RNA therapies for the treatment of patients with cancer.

Author Info: (1) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 065

Author Info: (1) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. (2) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (3) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (4) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (5) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. (6) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (7) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (8) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (9) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (10) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (11) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (12) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (13) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. (14) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. (15) Gennao Bio, Hopewell, NJ 08525, USA. (16) Gennao Bio, Hopewell, NJ 08525, USA. (17) Gennao Bio, Hopewell, NJ 08525, USA. (18) Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. Department of Urology, Akita University School of Medicine, Akita, 010-8543, Japan. (19) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. (20) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (21) Gennao Bio, Hopewell, NJ 08525, USA. (22) Gennao Bio, Hopewell, NJ 08525, USA. (23) Gennao Bio, Hopewell, NJ 08525, USA. (24) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (25) Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA. (26) Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. (27) Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA. Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (28) Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA. (29) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT 06520, USA. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. (30) Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.

Citation: Sci Transl Med 2025 Jul 16 17:eadk1868 Epub07/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40668891

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Design of high-specificity binders for peptide-MHC-I complexes Featured  

(1) Liu B (2) Greenwood NF (3) Bonzanini JE (4) Motmaen A (5) Meyerberg J (6) Dao T (7) Xiang X (8) Ault R (9) Sharp J (10) Wang C (11) Visani GM (12) Vafeados DK (13) Roullier N (14) Nourmohammad A (15) Scheinberg DA (16) Garcia KC (17) Baker D

Science

Liu, Greenwood, Bonzanini, et al. utilized new generative AI protein design platforms to identify binders to pMHCI complexes with high specificity, overcoming many of the challenges associated with identifying high-affinity and highly-specific TCRs. When incorporated into CARs expressed on T cells, these binders could effectively stimulate T cell activation and induce target-specific cell killing, demonstrating potential for use in immunotherapies.

(1) Liu B (2) Greenwood NF (3) Bonzanini JE (4) Motmaen A (5) Meyerberg J (6) Dao T (7) Xiang X (8) Ault R (9) Sharp J (10) Wang C (11) Visani GM (12) Vafeados DK (13) Roullier N (14) Nourmohammad A (15) Scheinberg DA (16) Garcia KC (17) Baker D

Science

Liu, Greenwood, Bonzanini, et al. utilized new generative AI protein design platforms to identify binders to pMHCI complexes with high specificity, overcoming many of the challenges associated with identifying high-affinity and highly-specific TCRs. When incorporated into CARs expressed on T cells, these binders could effectively stimulate T cell activation and induce target-specific cell killing, demonstrating potential for use in immunotherapies.

ABSTRACT: Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (2) Department of Biochemistry

Author Info: (1) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (2) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (3) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Bioengineering Graduate Program, University of Washington, Seattle, WA, USA. (4) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Bioengineering Graduate Program, University of Washington, Seattle, WA, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (10) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (11) Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA. (12) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (13) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. (14) Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, WA, USA. Department of Physics, University of Washington, Seattle, WA, USA. Department of Applied Mathematics, University of Washington, Seattle, WA, USA. Fred Hutchinson Cancer Center, Seattle, WA, USA. (15) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Cornell Medicine, New York, NY, USA. (16) Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA. (17) Department of Biochemistry, University of Washington, Seattle, WA, USA. Institute for Protein Design, University of Washington, Seattle, WA, USA. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.

Citation: Science 2025 Jul 24 389:386-391 Epub07/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40705892

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IL-12 mRNA-LNP promotes dermal resident memory CD4+ T cell development

Spotlight 

(1) Zabala-Peñafiel A (2) Gonzalez-Lombana C (3) Alameh MG (4) Sacramento LA (5) Mou Z (6) Phan AT (7) Aunins EA (8) Tam YK (9) Uzonna JE (10) Weissman D (11) Hunter CA (12) Scott P

NPJ vaccines | Free PMC Article

Zabala-Peñafiel, Gonzalez-Lombana et al. showed that mice vaccinated s.c. with LNPs containing mRNA encoding leishmanial PEPCK antigen generated specific dLN and splenic Th1 and T follicular helper cells, but few dermal resident memory T cells (dTrm). These mice did not mount delayed-type hypersensitivity (DTH, which requires dTrm in non-inflamed skin) or protective responses to L. major intradermal infection. Delivering IL-12 mRNA-LNPs with PEPCK vaccines boosted levels of specific Th1 cells with skin-homing (selectin+) and memory markers in LN, increased dTrm cells in inflamed and non-inflamed skin, and induced DTH and protective responses to Leishmania challenge.

Contributed by Paula Hochman

(1) Zabala-Peñafiel A (2) Gonzalez-Lombana C (3) Alameh MG (4) Sacramento LA (5) Mou Z (6) Phan AT (7) Aunins EA (8) Tam YK (9) Uzonna JE (10) Weissman D (11) Hunter CA (12) Scott P

NPJ vaccines | Free PMC Article

Zabala-Peñafiel, Gonzalez-Lombana et al. showed that mice vaccinated s.c. with LNPs containing mRNA encoding leishmanial PEPCK antigen generated specific dLN and splenic Th1 and T follicular helper cells, but few dermal resident memory T cells (dTrm). These mice did not mount delayed-type hypersensitivity (DTH, which requires dTrm in non-inflamed skin) or protective responses to L. major intradermal infection. Delivering IL-12 mRNA-LNPs with PEPCK vaccines boosted levels of specific Th1 cells with skin-homing (selectin+) and memory markers in LN, increased dTrm cells in inflamed and non-inflamed skin, and induced DTH and protective responses to Leishmania challenge.

Contributed by Paula Hochman

ABSTRACT: Dermal resident memory CD4(+) T cells (dTrm) provide protection against vector-borne infections. However, the factors that promote their development remain unclear. We tested if an mRNA vaccine, encoding a protective leishmanial antigen, induced dTrm cells. The mRNA vaccine induced robust systemic T-cell responses, but few Trm cells were found in the skin. Since IL-12 promotes Th1 responses, we tested whether IL-12 mRNA combined with the mRNA vaccine could enhance dTrm cell development. This combination significantly expanded Leishmania-specific Th1 cells expressing skin-homing molecules and memory T cell markers in the draining lymph node. Additionally, higher numbers of dTrm cells were maintained in the skin, and mice exhibited functional immunity indicated by a delayed hypersensitivity response and protection upon challenge with Leishmania. These findings highlight IL-12 as a key driver of CD4(+) dTrm development, enabling their global seeding across the skin, and underscore the potential of IL-12-enhanced mRNA vaccines to generate durable immunity against cutaneous leishmaniasis and other skin-targeted infections.

Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, Uni

Author Info: (1) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada. (6) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8) Acuitas Therapeutics, Vancouver, BC, Canada. (9) Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada. (10) Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Penn Institute for RNA Innovation, University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. pscott@upenn.edu.

Citation: NPJ Vaccines 2025 Jul 16 10:154 Epub07/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40670370

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De novo-designed pMHC binders facilitate T cell-mediated cytotoxicity toward cancer cells Spotlight 

(1) Johansen KH (2) Wolff DS (3) Scapolo B (4) Fernández-Quintero ML (5) Risager Christensen C (6) Loeffler JR (7) Rivera-de-Torre E (8) Overath MD (9) Kjærgaard Munk K (10) Morell O (11) Viuff MC (12) Lacunza I (13) Damm Englund AT (14) Due M (15) Gharpure A (16) Forli S (17) Rodriguez Pardo C (18) Tamhane T (19) Qingjie Andersen E (20) Haldrup Björnsson K (21) Fernandes JS (22) Voss LF (23) Thumtecho S (24) Ward AB (25) Ormhøj M (26) Reker Hadrup S (27) Jenkins TP

Science

Johansen, Wolff, Scapolo, et al. used a known crystal structure, RFdiffusion, and other generative models to rapidly de novo design high-affinity minibinders (miBds) targeting the NY-ESO-1 peptide SllMWITQC on HLA-A*02:01. In silico cross-panning and molecular dynamics simulations allowed prescreening of specificity, which was later confirmed in vitro. The miBd structure was validated through cryo-electron microscopy, and when incorporated as a CAR on T cells, miBd binding induced killing of NY-ESO-1+ melanoma cells. The researchers also designed and validated a miBd to a neoantigen pMHC complex for which no experimental structure was available.

Contributed by Lauren Hitchings

(1) Johansen KH (2) Wolff DS (3) Scapolo B (4) Fernández-Quintero ML (5) Risager Christensen C (6) Loeffler JR (7) Rivera-de-Torre E (8) Overath MD (9) Kjærgaard Munk K (10) Morell O (11) Viuff MC (12) Lacunza I (13) Damm Englund AT (14) Due M (15) Gharpure A (16) Forli S (17) Rodriguez Pardo C (18) Tamhane T (19) Qingjie Andersen E (20) Haldrup Björnsson K (21) Fernandes JS (22) Voss LF (23) Thumtecho S (24) Ward AB (25) Ormhøj M (26) Reker Hadrup S (27) Jenkins TP

Science

Johansen, Wolff, Scapolo, et al. used a known crystal structure, RFdiffusion, and other generative models to rapidly de novo design high-affinity minibinders (miBds) targeting the NY-ESO-1 peptide SllMWITQC on HLA-A*02:01. In silico cross-panning and molecular dynamics simulations allowed prescreening of specificity, which was later confirmed in vitro. The miBd structure was validated through cryo-electron microscopy, and when incorporated as a CAR on T cells, miBd binding induced killing of NY-ESO-1+ melanoma cells. The researchers also designed and validated a miBd to a neoantigen pMHC complex for which no experimental structure was available.

Contributed by Lauren Hitchings

ABSTRACT: The recognition of intracellular antigens by CD8(+) T cells through T cell receptors (TCRs) is central for adaptive immunity against infections and cancer. However, the identification of TCRs from patient material remains complex. We present a rapid de novo minibinder (miBd) design platform leveraging state-of-the-art generative models to engineer miBds targeting the cancer-associated peptide-bound major histocompatibility complex (pMHC) SLLMWITQC/HLA-A*02:01 (NY-ESO-1). Incorporating in silico cross-panning enabled computational prescreening of specificity, and molecular dynamics simulations allowed for improved predictability of in vitro success. We identified a high-affinity NY-ESO-1 binder and confirmed its structure using cryo-electron microscopy, which, when incorporated in a chimeric antigen receptor, induced killing of NY-ESO-1(+) melanoma cells. We further designed and validated binders to a neoantigen pMHC complex, RVTDESILSY/HLA-A*01:01, with unknown structure, demonstrating the potential for precision immunotherapy.

Author Info: (1) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (2) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kon

Author Info: (1) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (2) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (3) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (4) Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. (5) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (6) Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. (7) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (8) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (9) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (10) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (11) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (12) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (13) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (14) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (15) Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. (16) Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. (17) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (18) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (19) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (20) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (21) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (22) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (23) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark. (24) Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA. (25) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (26) Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark. (27) Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

Citation: Science 2025 Jul 24 389:380-385 Epub07/24/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40705893

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