Journal Articles

Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot Spotlight 

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

ABSTRACT: Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, "cold" tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)-based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert "cold" tumors into inflamed "hot" lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed "hot" phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell-redirecting therapies, in challenging tumor settings.

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Swit

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Switzerland. (3) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (4) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (5) Philochem AG, Otelfingen, Switzerland. (6) Philochem AG, Otelfingen, Switzerland. (7) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (8) Philochem AG, Otelfingen, Switzerland. (9) Philochem AG, Otelfingen, Switzerland. Philogen SpA, Siena, Italy. (10) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 Philogen SpA, Siena, Italy. (11) Philochem AG, Otelfingen, Switzerland.

Citation: Cancer Immunol Res 2026 Apr 21 OF1-OF14 Epub04/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42012522

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The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion Spotlight 

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

(1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

Developmental cell

Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

Contributed by Shishir Pant

ABSTRACT: The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical O

Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (3) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (5) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (6) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (7) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (8) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (9) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (11) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (12) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (13) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (14) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. (15) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (16) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (17) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (18) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (19) Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, USA. (20) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (21) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (22) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (23) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (24) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (25) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (26) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (27) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (28) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (29) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.

Citation: Dev Cell 2026 Apr 28 Epub04/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42055006

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Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity

Spotlight 

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

ABSTRACT: A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krppel-like factor 2 (KLF2) as a top TF driving CX3CR1(+) effector-like exhausted cell (Tex(eff-like)) differentiation. Overexpression of KLF2 converted CX3CR1_ cells into Tex(eff-like) cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8(+) T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Tex(eff-like) program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, X

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (2) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (3) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (4) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (5) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (6) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (7) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (8) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (9) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (10) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (11) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (13) Department of Pharmacy, Xiamen Medical College, Xiamen, Fujian 361023, China. (14) Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. (15) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (16) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (17) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (19) School of Medicine, Xiamen University, South Xiang'an Road, Xiamen, Fujian 361102, China. (20) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (21) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (22) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (23) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: honglinghuang@xmu.edu.cn.

Citation: Immunity 2026 Apr 27 Epub04/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42049034

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Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity Spotlight 

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

ABSTRACT: Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (AT(EVs)) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. AT(EV)-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EV(DNA)), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by AT(EVs) disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EV(DNA) encoding APP genes. DNase treatment removes most AT-EV(DNA), abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, AT(EVs) hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by AT(EVs) that boosts APP and anti-tumor immunity while limiting autoimmunity.

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. (2) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (5) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Systems Biology, Columbia University, New York, NY, USA. (8) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. (10) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linkšping University, Linkšping, Sweden. (11) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (12) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (13) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (14) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (15) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (16) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (17) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (19) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (20) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (21) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (23) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (24) Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA. (25) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (27) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Pathology, University of California, San Diego, La Jolla, CA, USA. (29) Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium. (30) Laboratory of Biology of Tumor and Development, UniversitŽ de Lige, Lige, Belgium. (31) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (32) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (33) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA. (34) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (35) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (37) Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (38) Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA. (39) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (40) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (41) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. (42) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (43) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: haz2005@med.cornell.edu. (44) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: irm2224@med.cornell.edu. (45) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

Citation: Cancer Cell 2026 Apr 30 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066762

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Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection Spotlight 

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

ABSTRACT: Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc_R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc_R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc_R III or inhibitory Fc_R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc_R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc_R-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. CHA Biotech, CHA Bio Complex, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California, San Francisco, CA 94143. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (8) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (9) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (13) Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (14) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (16) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322. (17) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA (18) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (20) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322.

Citation: Proc Natl Acad Sci U S A 2026 Apr 14 123:e2427192123 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41950082

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Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors

Featured  

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

ABSTRACT: Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (T(reg) cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I(+) cancers that expressed NKG2D ligands. T(reg) cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-T(reg) cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-T(reg) cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of T(reg) cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of T(reg) cells in tumors can control CD8 T cell-resistant cancers.

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electric

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (7) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (8) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (9) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (10) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (11) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (12) Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94305, USA. (13) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (14) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (15) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Citation: Sci Immunol 2026 Apr 10 11:eadx4411 Epub04/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41961946

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Spleen-targeted neoantigen mRNA vaccine induces ISG15+ CD8+ T cell-mediated tertiary lymphoid structure formation in hepatocellular carcinoma

Spotlight 

(1) Lin X (2) Chen G (3) Tang R (4) Wu M (5) Zhang D (6) Lin F (7) Guan J (8) Yang J (9) Dong X (10) Zheng X (11) Qiu L (12) Yu H (13) Cai Z (14) Liu X

Cell reports. Medicine

Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens.

Contributed by Shishir Pant

(1) Lin X (2) Chen G (3) Tang R (4) Wu M (5) Zhang D (6) Lin F (7) Guan J (8) Yang J (9) Dong X (10) Zheng X (11) Qiu L (12) Yu H (13) Cai Z (14) Liu X

Cell reports. Medicine

Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens.

Contributed by Shishir Pant

ABSTRACT: The efficacy of neoantigen vaccine for advanced hepatocellular carcinoma (HCC) is limited largely due to insufficient T cell mobilization and activation. Herein, we develop a spleen-targeted neoantigen mRNA vaccine (STNvac) with highly efficient spleen-selective mRNA transfection. Using a three-dose vaccination regimen, STNvac demonstrates remarkable therapeutic efficacy in orthotopic HCC model with a high likelihood of complete tumor regression and significantly improved survival rates (p < 0.0001). Notably, we identify a distinct ISG15(+) CD8(+) T cell population as crucial mediators of STNvac-induced immunity with potent antigen-processing and cytotoxic capacities. Intriguingly, STNvac promotes the formation of tertiary lymphoid structures (TLSs) through GZMA-F2R-mediated interactions between ISG15(+) CD8(+) T cells and antigen-presenting cells (APCs), which is also confirmed in HCC patients. Taken together, our findings demonstrate the potent antitumor efficacy of spleen-targeted mRNA vaccine and reveal its underlying immune cell interactive mechanisms, presenting high potential for clinical translation.

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 35000

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (2) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (5) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (6) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (12) State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. (13) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: caizhixiong1985@163.com. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: xiaoloong.liu@gmail.com.

Citation: Cell Rep Med 2026 Apr 20 102754 Epub04/20/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42013842

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Allogeneic CD19 CAR T cells armed with an anti-rejection CD70 CAR overcome antigen escape and evade alloimmune responses Spotlight 

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

(1) Zhang K (2) Li Z (3) O'Dair MK (4) Qu D (5) Mealy AK (6) Nguyen D (7) Cheng HY (8) Huang D (9) Gopalakrishnan S (10) Roberts ZJ (11) Sommer C (12) Lauron EJ

Nature communications

Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells eliminated B cells and CD70(+) T cells derived from patients with systemic lupus erythematosus in humanized mouse models, resulting in reduced immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore broaden clinical applicability while enabling the use of less intensive lymphodepleting conditioning regimens prior to CAR T cell infusion.

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA,

Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA, USA. (4) Allogene Therapeutics Inc., South San Francisco, CA, USA. (5) Allogene Therapeutics Inc., South San Francisco, CA, USA. (6) Allogene Therapeutics Inc., South San Francisco, CA, USA. (7) Allogene Therapeutics Inc., South San Francisco, CA, USA. (8) Allogene Therapeutics Inc., South San Francisco, CA, USA. (9) Allogene Therapeutics Inc., South San Francisco, CA, USA. (10) Allogene Therapeutics Inc., South San Francisco, CA, USA. (11) Allogene Therapeutics Inc., South San Francisco, CA, USA. cesar.sommer@allogene.com. (12) Allogene Therapeutics Inc., South San Francisco, CA, USA. elvin.lauron@allogene.com.

Citation: Nat Commun 2026 Apr 12 Epub04/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41965340

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Identification of cycling regulatory T cell precursors as conductors of immune escape during breast carcinoma progression Spotlight 

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

(1) Bui TM (2) Jimenez ER (3) Li Z (4) Foidart P (5) Puleo J (6) Yan P (7) Jhaveri A (8) Yang L (9) Nishida J (10) Seehawer M (11) Cai X (12) Parker KA (13) Qin X (14) Sumer OE (15) Huang XY (16) Patel A (17) Dillon D (18) McDonnell CH 3rd (19) Rowberry R (20) Jhajj S (21) Baker C (22) Brown DD (23) Strand SH (24) Marks JR (25) Colditz GA (26) Park SY (27) Lee AV (28) Angelo M (29) McAuliffe PF (30) Bobolis K (31) West R (32) Dranoff G (33) Hwang ES (34) Cristea S (35) Polyak K

Cancer cell

Using single-cell and spatial transcriptomics in human and rat models, Bui et al. mapped immune remodeling of normal breast, pre-malignant (DCIS) , and invasive (IBC) breast cancer and identified a proliferative FOXP3int MKI67hi cycling Treg (cycTreg) subset. CycTregs emerged at the DCIS-IBC junction, expanded in IBC, and predicted CD8+ infiltration, TCR diversity, disease-specific survival, and DCIS recurrence. CycTreg abundance correlated with CLEC10A+ cDC2s, high HLA class II, and IL-33-producing CAFs. OX40 agonism plus anti-PD-L1 or IL-33 blockade reduced cycTreg, remodeled CAF states, and restored antitumor immunosurveillance.

Contributed by Shishir Pant

ABSTRACT: Immune escape during the ductal carcinoma in situ (DCIS)-to-invasive breast cancer (IBC) transition shapes tumor evolution. Through transcriptomic mapping of the immune landscapes of normal breast, DCIS, and IBC from large patient cohorts, we identified T and myeloid cells as the primary distinguishing features between DCIS and IBC. We discovered cycling regulatory T cells (cycTreg) as an orchestrator of immunosuppression in IBC. cycTreg frequency predicts cytotoxic CD8(+), TCR diversity, disease-specific survival in IBC, and recurrence in DCIS. In a rat model of breast cancer, we demonstrated that cycTreg act as precursors to mature Treg and are inducible by tumor-localized type 2 dendritic cells. Profiling of tumors subjected to OX40 and PD-L1 therapies revealed an IL-33-mediated fibroblast-cycTreg signaling loop, the disruption of which enhances intratumoral antigen-experienced CD8(+) effectors and systemic immunosurveillance. Our study defines cycTreg as critical inducers of immune escape and promising immuno-oncology targets in breast cancer.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (7) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (8) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (11) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (12) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. (13) Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27705, USA. (14) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. (17) Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. (18) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (19) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (20) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (21) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (22) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA. (23) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (24) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (25) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63108, USA. (26) Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea. (27) Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (28) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (29) UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (30) Sutter Institute for Medical Research, Roseville, CA 95661, USA. (31) Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (33) Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA. (34) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. (35) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Citation: Cancer Cell 2026 Apr 16 Epub04/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41997138

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Self-adjuvanting α-helical polypeptide simultaneously delivers neoantigen mRNAs and activates dendritic cells to eradicate tumors

Spotlight 

(1) Han J (2) Zhou J (3) Dwivedy A (4) Xue T (5) Bhatta R (6) Liu Y (7) Nguyen D (8) Bo Y (9) Wang Y (10) Wang X (11) Xu M (12) Berry M (13) Bailey K (14) Irudayaraj J (15) Liu J (16) Chen Q (17) Nie S (18) Wang X (19) Wang H

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1.

Contributed by Ute Burkhardt

(1) Han J (2) Zhou J (3) Dwivedy A (4) Xue T (5) Bhatta R (6) Liu Y (7) Nguyen D (8) Bo Y (9) Wang Y (10) Wang X (11) Xu M (12) Berry M (13) Bailey K (14) Irudayaraj J (15) Liu J (16) Chen Q (17) Nie S (18) Wang X (19) Wang H

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Han, Zhou, and Dwivedy et al. developed cationic α-helical polypeptides that can condense and stabilize encoding mRNA in nanosized polyplexes. Upon s.c. administration, these polyplexes are taken up by DCs in lymph nodes, induce activation by NF-κB, IRF, p-STING, and cGAS, and improve the processing and presentation of mRNA-encoded antigens compared to mRNA-LNP, lipoplexes, or free mRNA. In E.G7-OVA lymphoma and 4T1 TNBC models, polyplexes elicited potent neoantigen-specific CD8+ T cells, reprogrammed the TIME (enriching DCs, CD86+ macrophages, and CD8+ T cells), enhanced therapeutic efficacy, and synergized with anti-PD-1.

Contributed by Ute Burkhardt

ABSTRACT: mRNA-based vaccines have demonstrated tremendous success during the era of COVID-19, but its therapeutic potential for treating cancer, especially poorly immunogenic solid tumors, remains largely underachieved. Herein, we report a class of self-adjuvanting α-helical polypeptides that can dramatically improve the antitumor efficacy of tumor neoantigen-encoding mRNAs. The α-helical polypeptides can facilitate the intracellular delivery of mRNAs into dendritic cells (DCs), simultaneously activate DCs by regulating NF-κB and IRF pathways, and improve the ability of dendritic cells to process and present mRNA-encoded neoantigens. Molecular docking and simulation results also confirm the stable complexation between mRNA and α-helical polypeptides. The conceived polyplex, upon subcutaneous administration, can migrate to the draining lymph nodes and transfect and activate DCs in the lymph nodes, resulting in superior neoantigen-specific cytotoxic T lymphocyte response in vivo. Compared to conventional lipoplexes or SM102 lipid nanoparticle-based mRNA vaccines that yield 0% tumor-free survival, the polyplex yields 83.3% and 33.3% tumor-free survival against E.G7-OVA lymphoma and 4T1 triple negative breast cancer, respectively, among the best antitumor efficacy reported to date for mRNA cancer vaccines. The polyplex also reprograms the immunosuppressive tumor microenvironment, by stimulating and enriching DCs, M1-phenotype CD86+ macrophages, and CD8+ T cells in the tumors. We also observed the upregulated expression of Programmed Death-1 (PD-1) by intratumoral CD8+ T cells and PD-L1 by 4T1 tumor cells after polyplex treatment and further demonstrated the synergistic effect between polyplex vaccine and anti-PD-1 therapy. Our polyplex system provides a facile and generalizable approach to developing robust mRNA-based cancer vaccines.

Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University o

Author Info: (1) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (2) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (3) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (4) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (5) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (6) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (7) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (8) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (9) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (10) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (11) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (12) Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (13) Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142. (14) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL (15) Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining 314400, China. (16) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (17) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (18) Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. (19) Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Cancer Center at Illinois, Urbana, IL 61801. Carle College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

Citation: Proc Natl Acad Sci U S A 2026 Apr 21 123:e2504976123 Epub04/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41984833

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