Journal Articles

Reprogramming CAR with cytokine signaling increases the efficacy of CAR-T cell therapy in solid tumour treatment and confers sustained immune memory

(1) Sun R (2) Liu S (3) Yang X (4) Che C (5) Zhang Z (6) Zhang C (7) Wang Y (8) Yang Y (9) Li X (10) Wang J (11) Zheng H (12) Guo M (13) Yin H

Cancer immunology research

To improve CAR T cell efficacy for solid tumors, Sun and Liu et al. designed a series of CARs that enabled antigen-dependent “cytokine” co-activation, while preserving second-generation CAR structure. Incorporating compact IL-2/IL-15 receptor (IL2RB)-derived STAT5 docking motifs (Y392 and Y510) within the CD3ζITAM2/3 regions resulted in antigen-specific co-activation upon CAR engagement. The best candidate S71 CAR exhibited superior efficacy and dose-dependent memory in multiple xenograft tumor models (EDB-fibronectin, CD19, and CLDN), improved mitochondrial function, and supported durable and persistent T cell activity, with less exhaustion.

Contributed by Katherine Turner

(1) Sun R (2) Liu S (3) Yang X (4) Che C (5) Zhang Z (6) Zhang C (7) Wang Y (8) Yang Y (9) Li X (10) Wang J (11) Zheng H (12) Guo M (13) Yin H

Cancer immunology research

To improve CAR T cell efficacy for solid tumors, Sun and Liu et al. designed a series of CARs that enabled antigen-dependent “cytokine” co-activation, while preserving second-generation CAR structure. Incorporating compact IL-2/IL-15 receptor (IL2RB)-derived STAT5 docking motifs (Y392 and Y510) within the CD3ζITAM2/3 regions resulted in antigen-specific co-activation upon CAR engagement. The best candidate S71 CAR exhibited superior efficacy and dose-dependent memory in multiple xenograft tumor models (EDB-fibronectin, CD19, and CLDN), improved mitochondrial function, and supported durable and persistent T cell activity, with less exhaustion.

Contributed by Katherine Turner

ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in hematologic malignancies but remains limited in solid tumors because of the immunosuppressive microenvironment, tumor heterogeneity, poor immune-cell infiltration, and progressive T-cell dysfunction. Because cytokine costimulation is critical for maintaining T-cell fitness, we developed a modular engineering strategy, distinct from previous approaches based on direct insertion of large cytokine receptor fragments, in which the intracellular CAR signaling domain was reconstructed to incorporate compact IL-2/IL-15 receptor-derived activation motifs, thereby enabling antigen-dependent coactivation while preserving the overall architecture of the parental CAR. Through systematic screening, we identified S71 as the optimal construct, with significantly greater antitumor activity than other mutants across multiple solid and hematologic tumor targets. Mechanistically, S71 rewired CAR signaling and reprogrammed tumor-induced metabolic responses through a self-sustaining mechanism, improving mitochondrial function and supporting durable T-cell activity. Functionally, S71 promoted enhanced persistence and robust immune memory responses against solid tumors. These findings demonstrate that modular integration of cytokine signaling motifs into CAR intracellular domains can improve CAR T-cell fitness and antitumor efficacy, and they establish S71 as a promising strategy for overcoming barriers to CAR T-cell therapy in solid tumors.

Author Info: (1) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (2) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (3) China Pharma

Author Info: (1) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (2) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (3) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (4) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (5) China Pharmaceutical University China. ROR: https://ror.org/01sfm2718 (6) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (7) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (8) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (9) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (10) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (11) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (12) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718 (13) China Pharmaceutical University Nanjing China. ROR: https://ror.org/01sfm2718

Citation: Cancer Immunol Res 2026 May 15 Epub05/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42139378

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

(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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Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models

(1) Gupta A (2) Das R (3) Reed K (4) Jeon T (5) Nguyen QTC (6) Rudra A (7) Ge X (8) Trongjit S (9) Vanrobaeys YS (10) Langer R (11) Weissleder R (12) Garris C (13) Anderson DG

Nature biotechnology

In mice, i.t. or i.v. delivery of CKK-E12-LNPs loaded with immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase (NIK) or IFN regulatory factor 8 (IRF8) induced (1) APC activation and maturation into cDC1s, (2) a release of immunostimulatory cytokines, (3) accumulation of NKT and γδT cells in tumors, and (4) priming of antitumor CD8+ T cells, which infiltrated and eliminated tumors and protected mice from rechallenge. In combination with mRNA encoding OVA, IR-mRNA prevented growth of OVA+ tumors. IR-mRNAs also synergized with anti-PD-1, and enhanced humoral and adaptive immune responses to infectious disease antigens.

Contributed by Lauren Hitchings

(1) Gupta A (2) Das R (3) Reed K (4) Jeon T (5) Nguyen QTC (6) Rudra A (7) Ge X (8) Trongjit S (9) Vanrobaeys YS (10) Langer R (11) Weissleder R (12) Garris C (13) Anderson DG

Nature biotechnology

In mice, i.t. or i.v. delivery of CKK-E12-LNPs loaded with immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase (NIK) or IFN regulatory factor 8 (IRF8) induced (1) APC activation and maturation into cDC1s, (2) a release of immunostimulatory cytokines, (3) accumulation of NKT and γδT cells in tumors, and (4) priming of antitumor CD8+ T cells, which infiltrated and eliminated tumors and protected mice from rechallenge. In combination with mRNA encoding OVA, IR-mRNA prevented growth of OVA+ tumors. IR-mRNAs also synergized with anti-PD-1, and enhanced humoral and adaptive immune responses to infectious disease antigens.

Contributed by Lauren Hitchings

ABSTRACT: Although immunotherapy has benefited a subset of persons with cancer, its broader efficacy remains limited, primarily because of an immunosuppressive tumor microenvironment characterized by insufficient numbers of functional tumor-specific T cells, antigen-presenting cells (APCs) and tumor-infiltrating lymphocytes. Here we engineer immune cells in the tumor microenvironment using lipid nanoparticles (LNPs) to deliver immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase or interferon regulatory factor 8. These IR-mRNAs activate APCs in tumors, significantly increasing activated type 1 conventional dendritic cells, immunostimulatory cytokines and priming antitumor CD8+ T cells. IR-mRNAs encapsulated in LNPs elicited durable antitumor responses in multiple syngeneic mouse tumor models through both intratumoral and intravenous delivery. Coadministration of IR-mRNA and ovalbumin mRNA elicited a ~10-fold increase in antigen-specific CD8+ T cell responses, sustained long-term memory and effectively prevented tumor growth in vaccinated mice. Additionally, coadministration of IR-mRNA and hemagglutinin mRNA enhanced the humoral response ~5-fold and the cellular response ~15-fold, underscoring their potential as adjuvants for boosting adaptive immunity.

Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute

Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. (3) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (5) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (6) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA. (7) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. (8) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (9) Bioinformatics & Computing Core Facility of the Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (10) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (11) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Department of Radiology, Massachusetts General Brigham, Boston, MA, USA. (12) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. cgarris@mgh.harvard.edu. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. cgarris@mgh.harvard.edu. (13) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

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

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42129506

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Differential assembly of mouse and human tumor microenvironments

(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

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

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

Science advances | Free PMC Article

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

Contributed by Katherine Turner

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

Science advances | Free PMC Article

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

Contributed by Katherine Turner

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

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

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

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

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

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

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

    Nature communications

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

    Contributed by Shishir Pant

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

    Nature communications

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

    Contributed by Shishir Pant

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

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

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

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

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

    Tags:

      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

      Tags:

        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

        Tags:

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

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

          Nature biomedical engineering

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

          Contributed by Lauren Hitchings

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

          Nature biomedical engineering

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

          Contributed by Lauren Hitchings

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

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

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

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

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

          Tags:
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