Journal Articles

Tumor irradiation promotes antigen dressing of dendritic cells to enhance CAR T cell persistence and efficacy in lung metastases Spotlight 

(1) Navarre S (2) Ishibashi MN (3) Nair A (4) Reyes-Torres I (5) Belabed M (6) Halasz L (7) Park MD (8) Mattiuz R (9) Ounadjela M (10) Gunset G (11) Mansilla-Soto J (12) Feucht J (13) Cabriolu A (14) Le Berichel J (15) Birbrair A (16) Eyquem J (17) Brown BD (18) Merad M (19) Sadelain M (20) Ahmed J

Nature cancer

Navarre, Ishibashi, and Nair et al. showed that focal 8 Gy tumor irradiation in a syngeneic metastatic lung adenocarcinoma model enhanced CAR T cell persistence and efficacy in a DC-dependent manner. Irradiation conditioned tumor cells for trogocytic antigen transfer onto DCs and macrophages, but only DCs engaged CAR T cells through the chimeric receptor, sustaining their activity. DC depletion abolished sustained CAR T cells and long-term tumor control. CAR T cell expansion was restricted to irradiated tumors, and not adjacent antigen-expressing normal lung tissue, indicating spatially restricted DC–CAR T cell engagement.

Contributed by Shishir Pant

(1) Navarre S (2) Ishibashi MN (3) Nair A (4) Reyes-Torres I (5) Belabed M (6) Halasz L (7) Park MD (8) Mattiuz R (9) Ounadjela M (10) Gunset G (11) Mansilla-Soto J (12) Feucht J (13) Cabriolu A (14) Le Berichel J (15) Birbrair A (16) Eyquem J (17) Brown BD (18) Merad M (19) Sadelain M (20) Ahmed J

Nature cancer

Navarre, Ishibashi, and Nair et al. showed that focal 8 Gy tumor irradiation in a syngeneic metastatic lung adenocarcinoma model enhanced CAR T cell persistence and efficacy in a DC-dependent manner. Irradiation conditioned tumor cells for trogocytic antigen transfer onto DCs and macrophages, but only DCs engaged CAR T cells through the chimeric receptor, sustaining their activity. DC depletion abolished sustained CAR T cells and long-term tumor control. CAR T cell expansion was restricted to irradiated tumors, and not adjacent antigen-expressing normal lung tissue, indicating spatially restricted DC–CAR T cell engagement.

Contributed by Shishir Pant

ABSTRACT: Metastatic solid tumors remain the principal cause of cancer mortality worldwide. High tumor burden impairs responses to chimeric antigen receptor (CAR) T cell therapy, yet off-tumor toxicity limits the doses that can be safely delivered. Strategies to selectively enhance CAR T cell activity at tumor sites could widen the therapeutic window. Using syngeneic models of extensive metastatic lung adenocarcinoma and melanoma, we show that 8_Gy of tumor irradiation significantly enhanced CAR T cell persistence in a manner critically dependent on dendritic cells (DCs). Irradiation promoted trogocytic antigen dressing of tumor antigens onto DCs, which then expanded CAR T cells through the chimeric receptor. Without functional DCs, irradiation failed to sustain CAR T cell persistence and tumors relapsed. Irradiation increased CAR T cell numbers within tumors but not in adjacent normal lung tissue that also expressed target antigen, conferring robust control of tumor without increased toxicity. These data define a mechanistic basis and rationale for combining radiotherapy with CAR T cell therapy.

Author Info: (1) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department

Author Info: (1) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Biomedical Engineering, The City College of New York, New York, NY, USA. (2) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (3) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (11) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. (12) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cluster of Excellence iFIT (EXC2180) 'Image-guided and Functionally Instructed Tumor Therapies', University Children's Hospital TŸbingen, TŸbingen, Germany. (13) Department of Medicine, Immunology Program, Gene Transfer and Somatic Cell Engineering Laboratory, Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (14) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Department of Dermatology, University of Wisconsin-Madison, Madison, WI, USA. (16) Department of Medicine-Division of Hematology and Oncology, Gladstone-UCSF Institute of Genomic Immunology, Parker Institute for Cancer Immunotherapy, University of California, San Francisco, CA, USA. (17) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (18) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (19) Columbia Initiative in Cell Engineering and Therapy (CICET), Cancer Cell Therapy Initiative in the Vagelos Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. (20) Department of Immunology and Immunotherapy, Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jalal.ahmed@mountsinai.org. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jalal.ahmed@mountsinai.org.

Citation: Nat Cancer 2026 May 22 Epub05/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42174275

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Differential assembly of mouse and human tumor microenvironments Spotlight 

(1) Courau T (2) Jaszczak RG (3) Samad B (4) Flynn E (5) Chew NW (6) Reeder GC (7) Tsui J (8) Teklu S (9) Pass LF (10) Edwards AW (11) Naser M (12) Ray A (13) Wismer H (14) Bunis D (15) Lupin-Jimenez L (16) Gavil NV (17) Masopust D (18) Graham JP (19) Skelly DA (20) Vesco X (21) Liu ET (22) Fragiadakis GK (23) Combes AJ (24) Krummel MF

Nature immunology

Courau et al. profiled immune landscapes of 15 common mouse tumor models alongside human datasets. Most murine TIMEs resembled a minority subset of macrophage-rich, poorly infiltrated human tumors. Cross-species analysis showed species-specific biases in chemokine networks (including reduced CCR2/CCR5 and altered CXCL13 in mice) and altered T and myeloid cell frequencies, while conserved cell-type specific gene expression programs emerged as discriminatory. An IFN-responsive myeloid–CD8+ T cell cytotoxicity module was conserved across tumor types, and predicted clinical outcome in humans.

Contributed by Shishir Pant

(1) Courau T (2) Jaszczak RG (3) Samad B (4) Flynn E (5) Chew NW (6) Reeder GC (7) Tsui J (8) Teklu S (9) Pass LF (10) Edwards AW (11) Naser M (12) Ray A (13) Wismer H (14) Bunis D (15) Lupin-Jimenez L (16) Gavil NV (17) Masopust D (18) Graham JP (19) Skelly DA (20) Vesco X (21) Liu ET (22) Fragiadakis GK (23) Combes AJ (24) Krummel MF

Nature immunology

Courau et al. profiled immune landscapes of 15 common mouse tumor models alongside human datasets. Most murine TIMEs resembled a minority subset of macrophage-rich, poorly infiltrated human tumors. Cross-species analysis showed species-specific biases in chemokine networks (including reduced CCR2/CCR5 and altered CXCL13 in mice) and altered T and myeloid cell frequencies, while conserved cell-type specific gene expression programs emerged as discriminatory. An IFN-responsive myeloid–CD8+ T cell cytotoxicity module was conserved across tumor types, and predicted clinical outcome in humans.

Contributed by Shishir Pant

ABSTRACT: Mouse models are frequently used to develop treatments for human cancer. However, the degree to which their tumor microenvironments (TMEs) are synonymously assembled is particularly poorly characterized. Through systematic immunoprofiling of 15 commonly used mouse models, we found that most murine TMEs recapitulate the composition of poorly infiltrated human tumors, extensively biased toward high macrophage densities. We discovered substantial species-specific biases of chemokine expression networks known to drive TMEs assembly, together with discoordinated frequencies of T and myeloid cell subtypes. Even with variable alignment, conserved cell-type-specific gene expression programs emerged across species and cohorts. Dissecting the coordinated T cell-myeloid gene expression programs revealed a conserved axis between interferon-responsive myeloid states and ongoing T cell cytotoxicity that transcends tissue of origin and predicts clinical outcome. Collectively, this work provides a practical atlas outlining both the hazards and opportunities of using mice to model human cancer.

Author Info: (1) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. tristan.courau@ucsf.edu. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. tristan.courau@u

Author Info: (1) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. tristan.courau@ucsf.edu. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. tristan.courau@ucsf.edu. CoLabs, UCSF, San Francisco, CA, USA. tristan.courau@ucsf.edu. (2) CoLabs, UCSF, San Francisco, CA, USA. (3) ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. (4) CoLabs, UCSF, San Francisco, CA, USA. (5) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. (6) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. (7) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. (8) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. (9) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. (10) CoLabs, UCSF, San Francisco, CA, USA. (11) CoLabs, UCSF, San Francisco, CA, USA. (12) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. (13) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. (14) CoLabs, UCSF, San Francisco, CA, USA. (15) CoLabs, UCSF, San Francisco, CA, USA. (16) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (17) Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA. (18) The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA. (19) The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA. (20) The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA. (21) The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. (22) CoLabs, UCSF, San Francisco, CA, USA. Department of Medicine, Division of Rheumatology, UCSF, San Francisco, CA, USA. (23) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. CoLabs, UCSF, San Francisco, CA, USA. Department of Medicine, Division of Gastroenterology, UCSF, San Francisco, CA, USA. (24) Department of Pathology and ImmunoX Initiative, UCSF, San Francisco, CA, USA. max.krummel@ucsf.edu. ImmunoProfiler Initiative, UCSF, San Francisco, CA, USA. max.krummel@ucsf.edu.

Citation: Nat Immunol 2026 May 19 Epub05/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42156893

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Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery Featured  

(1) Wang N (2) Yeh H (3) Lai B (4) Perera J (5) Jude KM (6) Risch I (7) Um J (8) Chen X (9) Xiang X (10) Wang C (11) Liu LD (12) Yang X (13) Paley MA (14) Khan AA (15) Garcia KC

Nature biotechnology

Using high-throughput yeast display and protein language models (pLMs), Wang, Yeh, et al. developed a new approach to determine TCR recognition that goes beyond the TCR sequence. This method generates deep peptide recognition profiles (PRPs), with PRP functional distance predicting the specificity of a new TCR, thereby enabling the discovery of novel candidate autoantigens in autoimmune disease.

(1) Wang N (2) Yeh H (3) Lai B (4) Perera J (5) Jude KM (6) Risch I (7) Um J (8) Chen X (9) Xiang X (10) Wang C (11) Liu LD (12) Yang X (13) Paley MA (14) Khan AA (15) Garcia KC

Nature biotechnology

Using high-throughput yeast display and protein language models (pLMs), Wang, Yeh, et al. developed a new approach to determine TCR recognition that goes beyond the TCR sequence. This method generates deep peptide recognition profiles (PRPs), with PRP functional distance predicting the specificity of a new TCR, thereby enabling the discovery of novel candidate autoantigens in autoimmune disease.

ABSTRACT: Predicting T cell receptor (TCR) specificity on the basis of sequence is challenging because TCRs of similar sequence can recognize entirely different antigens, whereas TCRs of different sequence can recognize the same antigens. Here we present a system that integrates high-throughput yeast display with fine-tuned protein language models (pLMs) to generate deep peptide recognition profiles (PRPs) for individual TCRs, each detailing binding against millions of peptides. We provide detailed PRPs for a panel of HLA-B*27:05-restricted TCRs from persons with ankylosing spondylitis and acute anterior uveitis that almost exclusively recognize peptides through CDR3β. pLMs trained on these PRPs outperform AlphaFold3 and tFold-TCR in predicting T cell activation. We discover and validate novel candidate autoantigens, demonstrate that model generalization to new TCRs correlates with functional distance (PRP divergence) rather than sequence similarity and introduce a model-intrinsic uncertainty metric to quantify prediction confidence. This system and its associated PRP datasets offer a scalable approach to mapping TCR recognition, accelerating antigen discovery and guiding TCR engineering.

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medic

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (2) Biohub, Chicago, IL, USA. Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Medical Scientist Training Program, University of Chicago, Chicago, IL, USA. (3) Biohub, Chicago, IL, USA. (4) Biohub, Chicago, IL, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (6) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (7) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (8) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (9) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Rheumatology Division, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. (14) Biohub, Chicago, IL, USA. aakhan@uchicago.edu. Departments of Pathology, and Family Medicine, University of Chicago, Chicago, IL, USA. aakhan@uchicago.edu. (15) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.

Citation: Nat Biotechnol 2026 May 13 Epub05/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42129507

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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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        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

        Tags:

          In vivo reprogramming of cytotoxic effector CD8+ T cells via fractalkine-conjugated mRNA-LNP

          Spotlight 

          Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

          Science immunology

          Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

          Contributed by Lauren Hitchings

          Angela R Corrigan 1, Shin Foong Ngiow 2 3 4, Maura Statzu 5, Amie Albertus 6, M Betina Pampena 1, Jayme M L Nordin 1, Stephen D Carro 7, Justin Harper 5, Rachelle L Stammen 8, Jennifer Wood 8, Houping Ni 6, Justin Su 6, Marziyeh Hajialyani 6, Vladimir V Shuvaev 6, Victor Alcalde 3, Mohammed-Alkhatim A Ali 3, Jacob T Hamilton 1, Rajesvaran Ramalingam 9, Vincent H Wu 1 10, Mirko Paiardini 5 11, Drew Weissman 6 12, E John Wherry 2 3 4, Edward F Kreider 6 12, Michael R Betts 1 12

          Science immunology

          Corrigan et al. developed and tested mRNA lipid nanoparticles (mRNA-LNP) conjugated with fractalkine (CX3CL1) and found that they were able to specifically target CX3CR1+ cells – primarily effector T cells and NK cells – inducing transient expression of the payload mRNA. Administration of fraktalkine-conjugated mRNA-LNPs could be used to induce secretion of IL-2 or cell membrane expression of CD62L in target cells in vivo, with detectable expression of payload expression in up to 95% and 100% of Teff in the peripheral blood of mice and rhesus macaques, respectively. CD62L expression may have enabled lymph node trafficking of CX3CR1+ Teff cells.

          Contributed by Lauren Hitchings

          ABSTRACT: Selective in vivo reprogramming of cytotoxic effector CD8 T (Teff) cells holds tremendous promise as a therapeutic tool but has not yet been accomplished. Here, we demonstrate that fractalkine-conjugated mRNA lipid nanoparticles (mRNA-LNPs) can specifically target and deliver mRNA to CX3CR1+ Teff cells in vitro and in vivo. In mice, fractalkine-conjugated mRNA-LNPs targeted up to 95% of blood and splenic Teff cells. In addition, delivery of IL-2-encoding mRNA and human CD62L-encoding mRNA to mouse Teff cells enabled robust exogenous IL-2 secretion and CD62L expression. In rhesus macaques, fractalkine-conjugated mRNA-LNPs targeted up to ~100% of peripheral blood Teff cells, and delivery of human CD62L-encoding mRNA enabled cell-surface human CD62L expression on peripheral blood Teff cells and detection of human CD62L+ Teff cells in lymphoid tissue. Collectively, these data demonstrate the potential of natural receptor ligand-based targeting of mRNA-LNPs for rapid, efficient, and transient in vivo modification of Teff cells.

          Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania

          Author Info: 1Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 4Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 6Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Division of Animal Resources, Emory National Primate Research Center, Emory University, Atlanta, GA, USA. 9Acuitas Therapeutics, Vancouver, Canada. 10Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, USA. 11Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. 12Center for AIDS Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

          Citation: Epub 2026 May 8.

          Link to PUBMED: https://pubmed.ncbi.nlm.nih.gov/42102231/

          Tags:

            Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer

            Spotlight 

            (1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

            Cancer cell

            Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

            Contributed by Shishir Pant

            (1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

            Cancer cell

            Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

            Contributed by Shishir Pant

            ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8(+) T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8(+) T cells or tumor cell MHC expression but instead requires IFN_-producing CD4(+) T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4(+) T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4(+) T cell-IFN_ axis could be efficacious in PDAC.

            Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farbe

            Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (2) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School Program in Virology, Boston, MA, USA. (3) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (6) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (7) Brookline High School, Brookline, MA, USA. (8) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (9) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (10) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (11) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (12) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (13) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (14) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (16) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (17) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (18) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (20) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (21) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (22) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, MA, USA. (24) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (27) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (28) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (30) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (31) Bristol Myers Squibb, Princeton, NJ, USA. (32) Bristol Myers Squibb, Princeton, NJ, USA. (33) Bristol Myers Squibb, Princeton, NJ, USA. (34) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (35) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (36) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

            Citation: Cancer Cell 2026 May 7 Epub05/07/2026

            Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102812

            Tags:

            Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways Spotlight 

            (1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

            Cancer cell

            Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

            Contributed by Lauren Hitchings

            (1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

            Cancer cell

            Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

            Contributed by Lauren Hitchings

            ABSTRACT: Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αEβ7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.

            Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Cent

            Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 20080, China; Breast and Thyroid Surgery Department, General Surgery Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (2) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (3) Department of Breast, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, No. 910 Hengshan Road, Shanghai, China. (4) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (5) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (6) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (7) Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 21500, China. (8) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (9) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (10) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (11) Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China. (12) Cancer Center, Faculty of Health Science, University of Macau, Macau 999078, China. (13) State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. (14) Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. (15) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (16) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (17) Department of Surgery, The Chinese University of Hong Kong Prince of Wales Hospital, Shatin 999077, Hong Kong SAR, China. (18) State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai 200031, China. (19) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. (20) Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (21) Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China. (22) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (23) Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: gem23@163.com. (24) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: drtaozhh@126.com. (25) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: liuwenting1015@163.com. (26) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. Electronic address: whx365@126.com.

            Citation: Cancer Cell 2026 May 7 Epub05/07/2026

            Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102811

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