Journal Articles

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

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

Nature biotechnology

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

Contributed by Ute Burkhardt

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

Nature biotechnology

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

Contributed by Ute Burkhardt

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

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

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

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

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

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

Spotlight 

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

Science

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

Contributed by Paula Hochman

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

Science

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

Contributed by Paula Hochman

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

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

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

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

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

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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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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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mRNA vaccines engage unconventional pathways in CD8+ T cell priming

Featured  

(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

(1) Jo S (2) Li L (3) Thakur C (4) Telfer KA (5) Sultan H (6) Ohara RA (7) He M (8) Nam G (9) Chen J (10) Ou F (11) Draghi M (12) Valiante NM (13) Schreiber RD (14) Randolph GJ (15) Saligrama N (16) Murphy TL (17) Gillanders WE (18) Murphy KM

Nature | Free PMC Article

Jo et al. investigated mechanisms of CD8+ T cell priming induced by mRNA-LNP vaccines. Priming occurred in lymphoid organs, using cDC1s and cDC2s as APCs. Cross-presentation was not a primary mechanism; instead, cross-dressing contributed to cDC2-induced priming, which was dependent on type I IFN signaling. CD8+ T cells primed this way exhibited antitumor activity, and functional memory cells were induced. cDC1 induced more cycling and stem-like populations, while cDC2 induced more clonally expanded terminal effector cells.

ABSTRACT: Vaccines composed of mRNA and lipid nanoparticles (LNPs) activate B cells and T cells by inducing in vivo production of specific protein antigens. While B cells can be activated directly by antigens, T cell activation requires antigen processing and presentation by MHC molecules on specialized antigen-presenting cells (APCs). In response to viral infections, tumours, and protein- and cDNA-based vaccines, antigen presentation to CD8(+) T cells is particularly dependent on type 1 conventional dendritic (cDC1) cells, which are specialized for efficient cross-presentation of exogenous antigens(1-4). However, whether similar mechanisms have a role in mRNA-LNP vaccination is unclear. Here we report that mRNA-LNP vaccines do not require cDC1 cells or the WDFY4-dependent cross-presentation pathway for CD8(+) T cell priming but instead engage both cDC1 and cDC2 cells redundantly. While CD8(+) T cells primed exclusively by either cDC1 or cDC2 cells showed phenotypic differences, both could mediate anti-tumour responses and memory formation. Importantly, acquisition by cDCs of peptide-MHC-I complexes from non-haematopoietic cells, called cross-dressing, provides a substantial component of CD8(+) T cell priming, in a manner dependent on type I interferon. mRNA-LNP induction of cross-dressing might explain their ability to activate CD8(+) T cells against antigens not encoded by the vaccine.

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis Sc

Author Info: (1) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (2) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. (3) Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. (4) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (5) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (6) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (7) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (8) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (9) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (10) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (11) Innovac Therapeutics, Cambridge, MA, USA. (12) Innovac Therapeutics, Cambridge, MA, USA. (13) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. (14) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (15) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. (16) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. (17) Department of Surgery, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University in St Louis School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St Louis, MO, USA. gillandersw@wustl.edu. (18) Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA. kmurphy@wustl.edu.

Citation: Nature 2026 Apr 15 Epub04/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41986715

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Nonsense-mediated mRNA decay inhibition reshapes the cancer immunopeptidome Featured  

(1) Vendramin R (2) Fu H (3) Fernandez Patel S (4) Zhao Y (5) Qian D (6) Ligammari L (7) Bartok O (8) Greenberg P (9) Levy R (10) Castro A (11) Thakkar K (12) Murai J (13) Lu WT (14) Sng CCT (15) Weller C (16) Beattie G (17) Bhamra A (18) Farriol-Duran R (19) Karagianni D (20) Augustine M (21) Dijkstra KK (22) Pinder CL (23) Simpson BS (24) Cheung GW (25) Galvez-Cancino F (26) Vlckova P (27) Surinova S (28) Rodriguez-Justo M (29) Shah M (30) McGranahan N (31) Carlton JG (32) Gršnroos E (33) Reading JL (34) Samuels Y (35) Swanton C (36) Quezada SA (37) Litchfield K

Immunity

Vendramin, Fu, Fernandez Patel, Zhao, et al. investigated nonsense-mediated mRNA decay (NMD) in cancer, and detected high activity of this pathway in tumors, with lower scores associated with better ICB responses in clinical data. Inhibition of SMG1 reduced NMD activity and resulted in significant increases in immunogenic MHC-I-presented neoantigens. This resulted in improved antitumor immune responses and synergized with ICB in vivo.

(1) Vendramin R (2) Fu H (3) Fernandez Patel S (4) Zhao Y (5) Qian D (6) Ligammari L (7) Bartok O (8) Greenberg P (9) Levy R (10) Castro A (11) Thakkar K (12) Murai J (13) Lu WT (14) Sng CCT (15) Weller C (16) Beattie G (17) Bhamra A (18) Farriol-Duran R (19) Karagianni D (20) Augustine M (21) Dijkstra KK (22) Pinder CL (23) Simpson BS (24) Cheung GW (25) Galvez-Cancino F (26) Vlckova P (27) Surinova S (28) Rodriguez-Justo M (29) Shah M (30) McGranahan N (31) Carlton JG (32) Gršnroos E (33) Reading JL (34) Samuels Y (35) Swanton C (36) Quezada SA (37) Litchfield K

Immunity

Vendramin, Fu, Fernandez Patel, Zhao, et al. investigated nonsense-mediated mRNA decay (NMD) in cancer, and detected high activity of this pathway in tumors, with lower scores associated with better ICB responses in clinical data. Inhibition of SMG1 reduced NMD activity and resulted in significant increases in immunogenic MHC-I-presented neoantigens. This resulted in improved antitumor immune responses and synergized with ICB in vivo.

ABSTRACT: DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

Author Info: (1) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Inst

Author Info: (1) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: r.vendramin@ucl.ac.uk. (2) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK. (3) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK. (4) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (5) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (6) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (7) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (10) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (11) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (12) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Drug Discovery Technology Laboratories, Ono Pharmaceutical Co. Ltd., Osaka, Japan. (13) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, UK. (14) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (16) CRUK City of London Centre Single Cell Genomics Facility, University College London Cancer Institute, London, UK; Bioinformatics Hub, University College London Cancer Institute, London, UK. (17) Proteomics Research Translational Technology Platform, University College London Cancer Institute, London, UK. (18) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Barcelona Supercomputing Center (BSC), Barcelona, Spain; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK. (19) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK. (20) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Division of Medicine, University College London, London, UK. (21) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (22) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (23) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (24) Research Department of Haematology, University College London Cancer Institute, London, UK. (25) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK; Immune Regulation Lab, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (26) Organoid Translational Technology Platform, University College London Cancer Institute, London, UK. (27) Proteomics Research Translational Technology Platform, University College London Cancer Institute, London, UK. (28) Department of Research Pathology, University College London Cancer Institute, London, UK. (29) CRUK City of London Explant and Patient-Derived Xenograft Core, London, UK. (30) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK. (31) Organelle Dynamics Lab, School of Cancer & Pharmaceutical Sciences, King's College London, London, UK; Organelle Dynamics Lab, the Francis Crick Institute, London, UK. (32) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK. (33) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Pre-Cancer Immunology Lab, University College London Cancer Institute, London, UK. (34) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (35) Cancer Evolution and Genome Instability Lab, The Francis Crick Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: charles.swanton@crick.ac.uk. (36) CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Immune Regulation and Tumor Immunotherapy Group, University College London Cancer Institute, London, UK. Electronic address: s.quezada@ucl.ac.uk. (37) The Tumor Immunogenomics and Immunosurveillance Lab, University College London Cancer Institute, London, UK; CRUK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Electronic address: k.litchfield@ucl.ac.uk.

Citation: Immunity 2026 Apr 8 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41956098

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    Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity Spotlight 

    (1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

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

    Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

    Contributed by Shishir Pant

    (1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

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

    Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

    Contributed by Shishir Pant

    ABSTRACT: Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-_-catenin(active) mice, which model _-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3(-/-) mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

    Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health

    Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824. (2) Department of Computer Science and Engineering, School of Engineering and Computer Science, Oakland University, Rochester, MI 48309. (3) Institute for Molecular Medicine and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. (4) Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA 94143. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129. (5) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824.

    Citation: Proc Natl Acad Sci U S A 2026 Mar 24 123:e2518080123 Epub03/19/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855265

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    Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle-mediated mRNA delivery in preclinical models Featured  

    (1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z

    Science translational medicine

    Chen, Wang, et al. assessed how metabolic differences may impact lipid nanoparticle (LNP) delivery. In physiologic culture medium, LNP delivery was limited, due to the downregulation of amino acids. Amino acid supplementation (AAS) improved LNP delivery of mRNA cargo in vitro and in vivo. AAS was also found to be beneficial in two preclinical models: in a liver inflammation model for growth hormone delivery via LNPs, where it improved outcomes, and for the specific delivery of gene editing components by LNPs.

    (1) Chen K (2) Wang W (3) Lennon A (4) McClure RA (5) Vuchkovska A (6) Kelley SO (7) Wang Z

    Science translational medicine

    Chen, Wang, et al. assessed how metabolic differences may impact lipid nanoparticle (LNP) delivery. In physiologic culture medium, LNP delivery was limited, due to the downregulation of amino acids. Amino acid supplementation (AAS) improved LNP delivery of mRNA cargo in vitro and in vivo. AAS was also found to be beneficial in two preclinical models: in a liver inflammation model for growth hormone delivery via LNPs, where it improved outcomes, and for the specific delivery of gene editing components by LNPs.

    ABSTRACT: Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs. Using an in vitro system, we found that simulated physiologic metabolic conditions led to the down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier-mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

    Author Info: (1) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Biohub, Chicago, IL

    Author Info: (1) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (2) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. (3) Biohub, Chicago, IL 60642, USA. (4) Biohub, Chicago, IL 60642, USA. (5) cTRL Therapeutics, Chicago, IL 60642, USA. (6) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA. cTRL Therapeutics, Chicago, IL 60642, USA. Department of Chemistry, Weinberg College of Arts & Sciences, Northwestern University, Evanston, IL 60208, USA. Department of Biochemistry, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA. Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA. (7) Biohub, Chicago, IL 60642, USA. Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL 60208, USA.

    Citation: Sci Transl Med 2026 Mar 11 18:eadx4097 Epub03/11/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41811986

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    Engineering lipid nanoparticle-stabilized emulsions for spatiotemporal mRNA delivery and enhanced T cell immunity Spotlight 

    (1) Zhou Y (2) Gao W (3) Huang X (4) Yan Y (5) Wu S (6) Shan X (7) Chen S (8) Qiu M (9) Ma G (10) Xia Y

    Cell reports. Medicine

    As an alternative to conventional lipid nanoparticles (LNPs), Zhou, Gao, Huang, and Yan et al. developed a colloid-engineered, LNP-stabilized emulsion (LSE) that was preferentially taken up by APCs (rather than stromal cells or fibroblasts), enhancing chemokine-driven activation and localized antigen presentation while reducing off-target antigen expression and non-immune cell cross-presentation. LSE fostered Th1-polarizization, expanded the T cell repertoire, and increased IFNγ and IL-2, with responses lasting up to 300 days. In murine tumor models, LSE vaccines elicited protective and therapeutic antitumor immunity that enhanced survival.

    Contributed by Lauren Hitchings

    (1) Zhou Y (2) Gao W (3) Huang X (4) Yan Y (5) Wu S (6) Shan X (7) Chen S (8) Qiu M (9) Ma G (10) Xia Y

    Cell reports. Medicine

    As an alternative to conventional lipid nanoparticles (LNPs), Zhou, Gao, Huang, and Yan et al. developed a colloid-engineered, LNP-stabilized emulsion (LSE) that was preferentially taken up by APCs (rather than stromal cells or fibroblasts), enhancing chemokine-driven activation and localized antigen presentation while reducing off-target antigen expression and non-immune cell cross-presentation. LSE fostered Th1-polarizization, expanded the T cell repertoire, and increased IFNγ and IL-2, with responses lasting up to 300 days. In murine tumor models, LSE vaccines elicited protective and therapeutic antitumor immunity that enhanced survival.

    Contributed by Lauren Hitchings

    ABSTRACT: Achieving strong T cell responses remains a key challenge in mRNA vaccines and therapeutics. Here, we develop a colloid-engineered, lipid nanoparticle-stabilized emulsion (LSE) to study how spatiotemporal mRNA delivery influences immune dynamics. Multi-omic analyses (single-cell RNA sequencing [scRNA-seq], flow cytometry, and enzyme-linked immunosorbent assay [ELISA]) illustrate that LSE facilitates localizing mRNA to immunocytes, increasing antigen presentation while reducing off-target antigen secretion, and non-immune cell cross-presentation, which are key factors linked to T cell exhaustion in conventional LNP-based systems. This targeted delivery induces durable interferon (IFN)-γ+ and interleukin (IL)-2+ T cell responses lasting up to 300 days and expands the T cell repertoire in mice compared to the AS01-adjuvanted Shingrix vaccine. Furthermore, LSE elicits potent protective and therapeutic effects against B16-OVA and LLC-NY-ESO1 inoculation in mice. These results indicate the potential of spatially controlled mRNA delivery for enhanced mRNA vaccinations.

    Author Info: (1) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical E

    Author Info: (1) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (2) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (3) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (4) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (5) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China. (6) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (7) Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China. (8) Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China. (9) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (10) National Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 10090, China; School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: yfxia@ipe.ac.cn.

    Citation: Cell Rep Med 2026 Mar 17 7:102667 Epub

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41850240

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    Nous-209 neoantigen vaccine for cancer prevention in Lynch syndrome carriers: a phase 1b/2 trial Spotlight 

    (1) D'Alise AM (2) Willis J (3) Duzagac F (4) Hall MJ (5) Cruz-Correa M (6) Idos GE (7) Thirumurthi S (8) Ballester V (9) Leoni G (10) Garzia I (11) Antonucci L (12) De Marco L (13) Micarelli E (14) Deng N (15) Secl“ L (16) Gogov S (17) Dong W (18) Jack Lee J (19) Bowen CM (20) Vornik LA (21) Garcia-Gonzalez A (22) Reyes-Uribe L (23) Richmond E (24) Umar A (25) Brown PH (26) Sinha KM (27) Rodriguez LM (28) Scarselli E (29) Vilar E

    Nature medicine

    D’Alise and Willis et al. presented results from a phase 1b/2 single-arm trial of 45 Lynch syndrome (LS) carriers treated with Nous-209 – an IM, heterologous, prime/boost, virus-based vaccine encoding 209 frameshift peptides (FSPs) shared across neoplasms with microsatellite instability (MSI). Potent/durable vaccine-induced FSP-specific IFNγ-producing CD4+ and cytotoxic CD8+ T cell responses were observed in all 37 evaluable participants. Peptide–HLA predictions helped identify >100 FSPs, which were immunogenic in vitro and detected in datasets of LS MSI-high colorectal pre-cancers/cancers. The vaccine was safe, and no participants had advanced adenomas or CRC at the end of the study.

    Contributed by Paula Hochman

    (1) D'Alise AM (2) Willis J (3) Duzagac F (4) Hall MJ (5) Cruz-Correa M (6) Idos GE (7) Thirumurthi S (8) Ballester V (9) Leoni G (10) Garzia I (11) Antonucci L (12) De Marco L (13) Micarelli E (14) Deng N (15) Secl“ L (16) Gogov S (17) Dong W (18) Jack Lee J (19) Bowen CM (20) Vornik LA (21) Garcia-Gonzalez A (22) Reyes-Uribe L (23) Richmond E (24) Umar A (25) Brown PH (26) Sinha KM (27) Rodriguez LM (28) Scarselli E (29) Vilar E

    Nature medicine

    D’Alise and Willis et al. presented results from a phase 1b/2 single-arm trial of 45 Lynch syndrome (LS) carriers treated with Nous-209 – an IM, heterologous, prime/boost, virus-based vaccine encoding 209 frameshift peptides (FSPs) shared across neoplasms with microsatellite instability (MSI). Potent/durable vaccine-induced FSP-specific IFNγ-producing CD4+ and cytotoxic CD8+ T cell responses were observed in all 37 evaluable participants. Peptide–HLA predictions helped identify >100 FSPs, which were immunogenic in vitro and detected in datasets of LS MSI-high colorectal pre-cancers/cancers. The vaccine was safe, and no participants had advanced adenomas or CRC at the end of the study.

    Contributed by Paula Hochman

    ABSTRACT: Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting ~1 in 300 individuals, with an overall lifetime cancer risk as high as 80%. LS is caused by germline mutations in the DNA mismatch repair genes, leading to microsatellite instability (MSI) and accumulation of shared mutations. When these occur in coding regions, they generate frameshift peptides (FSPs). Nous-209 is a neoantigen-directed immunotherapy based on a heterologous prime boost using great ape adenovirus and modified vaccinia virus Ankara encoding 209 FSPs shared across MSI neoplasms. We present the results from cohort 1 of a phase 1b/2 single-arm trial of Nous-209 for cancer interception in LS carriers (n = 45). Safety and immunogenicity were coprimary endpoints. Safety was assessed in 45 participants. Vaccination was safe with no intervention-related serious adverse events (AEs). The most common AEs were injection-site reactions (any grade in 91% of participants after prime and 76% after boost with no grade 3) and fatigue (any grade in 80% after prime and 53% after boost with 4% grade 3 after prime or after boost). Neoantigen-specific immune responses were observed after vaccination in 100% of evaluable participants (n = 37), with induction of potent T cell immunity (mean response at peak of ~1,100 interferon-γ spot-forming cells per million peripheral blood mononuclear cells). The immune response was durable and detectable at 1 year in 85% of participants. Both CD8+ and CD4+ T cells were induced, recognizing multiple FSPs. Peptide-human leukocyte antigen predictions allowed the identification of >100 immunogenic FSPs with demonstration of cytotoxic activity in vitro. Immunogenic FSPs were found in independent datasets of LS MSI colorectal precancers and cancers. These results highlight Nous-209 ability to efficiently stimulate immunity against neoantigens in LS, supporting its development for cancer interception (ClinicalTrials.gov identifier: NCT05078866 ).

    Author Info: (1) Nouscom SRL, Rome, Italy. (2) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Clinical C

    Author Info: (1) Nouscom SRL, Rome, Italy. (2) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA. (5) University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA. (6) City of Hope Comprehensive Cancer Center, Duarte, CA, USA. (7) Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) University of Puerto Rico Medical Sciences Campus, San Juan, PR, USA. (9) Nouscom SRL, Rome, Italy. (10) Nouscom SRL, Rome, Italy. (11) Nouscom SRL, Rome, Italy. (12) Nouscom SRL, Rome, Italy. (13) Nouscom SRL, Rome, Italy. (14) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Nouscom SRL, Rome, Italy. (16) Nouscom AG, Basel, Switzerland. (17) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA. (24) Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA. (25) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA. Department of Surgery, Walter Reed National Military Medical Center, Bethesda, MD, USA. (28) Nouscom SRL, Rome, Italy. e.scarselli@nouscom.com. (29) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. EVilar@mdanderson.org.

    Citation: Nat Med 2026 Jan 16 Epub01/16/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41545594

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