Journal Articles

Engineered human iPSC-derived dendritic cells dressed with tumor MHC complexes as a cancer vaccine Spotlight 

(1) Xu H (2) Kamei C (3) Gškbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R

Cell stem cell

Xu et al. identified optimal and reproducible culture and cytokine conditions to create universal, human iPSC-derived DCs lacking HLA (B2m/CTIIA KO) and with a CCR7+ migratory DC phenotype. An exosome-inspired process with tumor cell vesicles was used to cross-dress these DCs with peptide:MHC complexes from tumor cells. Cross-dressing promoted antigen presentation and resistance to “non-self” killing by NK cells. With cell lines in vitro and in vivo, the cross-dressed DCs enhanced T cell cytotoxicity and tumor control. Personal cross-dressed vaccines in AML and ovarian cancer were cytolytic in vitro. PD-L1/2 knockout improved activity.

Contributed by Ed Fritsch

(1) Xu H (2) Kamei C (3) Gškbuget D (4) Du J (5) Barrero M (6) Wang L (7) Iwamoto Y (8) Soriano JM (9) Godding K (10) Wang B (11) Kwek SS (12) Nistor GI (13) Keirstead HS (14) Fong L (15) Kaneko S (16) Gaensler KML (17) Blelloch R

Cell stem cell

Xu et al. identified optimal and reproducible culture and cytokine conditions to create universal, human iPSC-derived DCs lacking HLA (B2m/CTIIA KO) and with a CCR7+ migratory DC phenotype. An exosome-inspired process with tumor cell vesicles was used to cross-dress these DCs with peptide:MHC complexes from tumor cells. Cross-dressing promoted antigen presentation and resistance to “non-self” killing by NK cells. With cell lines in vitro and in vivo, the cross-dressed DCs enhanced T cell cytotoxicity and tumor control. Personal cross-dressed vaccines in AML and ovarian cancer were cytolytic in vitro. PD-L1/2 knockout improved activity.

Contributed by Ed Fritsch

ABSTRACT: Autologous-derived dendritic cells (DCs) are a promising source for cell-based cancer vaccines. However, their therapeutic potential is challenged by the number and quality produced and the diversity of antigens presented. To address these limitations, we present an approach that involves differentiating universal MHC-deficient human-induced pluripotent stem cells (hiPSCs) into CCR7(+) migratory DCs. These DCs are subsequently "dressed" with the full repertoire of MHC-antigen complexes derived from tumor cell membranes, transforming an allogeneic substrate into a personalized cancer vaccine product. The resulting "TumorDressed" DCs effectively activate T cells against tumor antigens. Their function is diminished when CD80/86 is deleted but significantly enhanced by the loss of PD-L1/2. PD-L1/2-null TumorDressed DCs demonstrate robust priming of anti-tumor T cell-mediated cytotoxicity both in vitro and in vivo, including against primary hematologic and solid tumors with matching patient T cells. These findings provide proof of concept for a universal, scalable, adaptable, and off-the-shelf DC cancer vaccine platform.

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, Univ

Author Info: (1) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (2) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (3) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (4) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (5) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (6) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (7) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (8) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. (9) AIVITA Biomedical, Irvine, CA, USA. (10) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (11) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (12) AIVITA Biomedical, Irvine, CA, USA. (13) AIVITA Biomedical, Irvine, CA, USA. (14) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA; Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (15) Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan. (16) Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA. (17) Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Urology, University of California, San Francisco (UCSF), San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA. Electronic address: robert.blelloch@ucsf.edu.

Citation: Cell Stem Cell 2026 Aug 25 Epub08/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42641609

Tags:

Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome Featured  

(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG

Cancer immunology research

Chen, Pulido, et al. investigated how AIRE expression in tumor cells impacts antitumor immune responses using murine models. Overexpression of AIRE led to higher expression of self-proteins, MHC-I in the context of H-2Kb, and MHC-I-presented epitopes, whereas downregulation led to lower expression. Antitumor immunity could be induced by DC vaccines loaded with cell lysates of AIRE-overexpressing tumor cells, inducing CD8+ and CD4+ T cell responses. Therapeutic AIRE tumor expression could be induced with in vivo delivery of an AAV vector, which was effective in curing mice, and survival time was improved by subsequent ICB.

(1) Chen A (2) Pulido JS (3) Tonne J (4) Metko M (5) Thompson JM (6) Sangsuwannukul T (7) Chiriboga-Yerovi MP (8) Diaz RM (9) Webb MJ (10) Huff AL (11) Moore M (12) Schuelke MR (13) Irshad S (14) Appleton E (15) Melcher A (16) Kendall B (17) Vile RG

Cancer immunology research

Chen, Pulido, et al. investigated how AIRE expression in tumor cells impacts antitumor immune responses using murine models. Overexpression of AIRE led to higher expression of self-proteins, MHC-I in the context of H-2Kb, and MHC-I-presented epitopes, whereas downregulation led to lower expression. Antitumor immunity could be induced by DC vaccines loaded with cell lysates of AIRE-overexpressing tumor cells, inducing CD8+ and CD4+ T cell responses. Therapeutic AIRE tumor expression could be induced with in vivo delivery of an AAV vector, which was effective in curing mice, and survival time was improved by subsequent ICB.

ABSTRACT: T-cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary thymic epithelial cells (mTEC) of the thymus. AIRE induces expression of peripheral tissue-specific self-antigens for presentation to nave T cells to promote activation/deletion of autoreactive T cells. This traditional role of AIRE in mTECs is to prevent autoimmunity. Herein, we demonstrate that tumors mimic the role of AIRE in mTECs to evade immune rejection. We found that AIRE induced a profile of "selfness" at the RNA and protein levels which, when presented on major histocompatibility complexes, shielded the tumor from inherently self-tolerized T cells. Moreover, we describe an in vivo immunotherapy in which engineered changes in AIRE expression in tumor cells altered their profile of selfness, exposing both AIRE-modified and parental unmodified tumor cells to T-cell attack. Therefore, by re-setting the immunological selfness of cancer cells, this AIRE-mediated immunotherapy 1) converted a highly tolerized T-cell compartment into a tumor-reactive T-cell population; 2) conferred upon non-immunogenic tumors de novo sensitivity to immune checkpoint blockade; 3) removed the need to identify potentially immunogenic tumor-associated antigens as targets for generation of T-cell responses; and 4) lead to potent T cell-mediated rejection of aggressive, immunologically cold, non-immunogenic tumors. Patient RNA-sequencing data showed that expression of AIRE predicted response to immune therapies with a strong correlation between AIRE expression and markers of T-cell receptor signaling, suggesting our studies have therapeutic translational value.

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Ro

Author Info: (1) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (2) Wills Eye Hospital Philadelphia, PA United States. ROR: https://ror.org/03qygnx22 (3) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (4) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (5) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (6) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (7) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (8) Vyriad United States. (9) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (10) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (11) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (12) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03 (13) King's College London London United Kingdom. ROR: https://ror.org/0220mzb33 (14) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (15) Institute of Cancer Research London United Kingdom. ROR: https://ror.org/043jzw605 (16) Mayo Clinic Rochester, Minnesota United States. ROR: https://ror.org/02qp3tb03 (17) Mayo Clinic Rochester, MN United States. ROR: https://ror.org/02qp3tb03

Citation: Cancer Immunol Res 2026 Aug 26 Epub08/26/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42644627

Tags:

Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function Spotlight 

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

(1) Takacsi-Nagy O (2) Kasinathan S (3) Hartman A (4) Yin Y (5) Wu L (6) Chen AY (7) Moser LM (8) May AP (9) Reeder GC (10) Celallos Fuentes E (11) Kernick C (12) Lu J (13) McClellan AK (14) Raposo CJ (15) Terrall B (16) Theberath NE (17) Yan PK (18) Xu P (19) Sotillo E (20) Eyquem J (21) Mackall CL (22) Roth TL (23) Satpathy AT

Cell

Takacsi-Nagy et al. generated a library of synthetic T cell Transcription Factors (sTFs) through combinatorial assembly of AP-1 family TF subdomains. Expressed in CAR-T cells, certain sTFs improved CAR-T persistence/proliferation over natural TFs in a chronic stimulation assay. sTFs induced unique transcriptional and epigenetic T cell states from natural TFs, although their DNA binding sites were conserved. One combination (JUN-FOS-BATF) especially improved cytotoxicity and in vivo persistence. The most impactful subdomains did not correlate with natural expression levels. Recombination of ETS and FOX family TF domains was also effective.

Contributed by Alex Najibi

ABSTRACT: Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford Univer

Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (2) Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (5) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Department of Bioengineering, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (8) Program in Immunology, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (9) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (13) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (14) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (15) Department of Pathology, Stanford University, Stanford, CA, USA. (16) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA. (18) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. (19) Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (20) Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (21) Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. (22) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: troth@stanford.edu. (23) Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.

Citation: Cell 2026 Aug 19 Epub08/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42617595

Tags:

A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle-based mRNA vaccines Spotlight 

(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H

Science advances | Free PMC Article

Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.

Contributed by Katherine Turner

(1) Muro R (2) Wang S (3) Ito-Kureha T (4) Huynh HH (5) Kobiyama K (6) Sugita T (7) Okamoto K (8) Nakano K (9) Okamura T (10) Kubo M (11) Ishii KJ (12) Nitta T (13) Takayanagi H

Science advances | Free PMC Article

Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.

Contributed by Katherine Turner

ABSTRACT: Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Bi

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (2) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (3) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (4) Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (5) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, United States. (6) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (7) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Immune Network Research Unit, Institute for Frontier Science Initiative InFiniti, Kanazawa University, Kanazawa, Japan. (8) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (9) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (10) Kyoto University Immunomonitoring Center, Liaison Office, Kyoto University, Kyoto, Japan. Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (11) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. (12) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (13) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

Citation: Sci Adv 2026 Jul 17 12:eaec7827 Epub07/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42467780

Tags:

IL7-Receptor-Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia Spotlight 

(1) Hocine HR (2) Ganbaatar U (3) Amador-Molina A (4) Banerjee S (5) Misawa K (6) Rubino V (7) Ankola P (8) Fong C (9) Xiong Y (10) Vista WR (11) Bellis RY (12) Chintala NK (13) Curran KJ (14) Sulis ML (15) Park JH (16) Kung AL (17) Adusumilli PS

Nature communications

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

(1) Hocine HR (2) Ganbaatar U (3) Amador-Molina A (4) Banerjee S (5) Misawa K (6) Rubino V (7) Ankola P (8) Fong C (9) Xiong Y (10) Vista WR (11) Bellis RY (12) Chintala NK (13) Curran KJ (14) Sulis ML (15) Park JH (16) Kung AL (17) Adusumilli PS

Nature communications

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

ABSTRACT: On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL7 receptor (IL7R), which promotes resistance to chemotherapy and disease relapse, here we develop IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments. We establish the antitumor efficacy of CD127 CAR against T-ALL cells in vitro, in female mouse models of T-ALL, and against blasts from patients with T-ALL using the patients' own T cells transduced with CD127 CAR. Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells, albeit with fratricide of CAR T cells following eradication of CD127-overexpressing blasts. CRISPR-Cas9 knockout of CD127 eliminates fratricide at the risk of prolonged lymphopenia in vivo. To overcome fratricide, we investigate short-term ( < 7 days) co-culture with or without dasatinib, a tyrosine kinase inhibitor, versus a natural selection method (10 days) and demonstrate that co-culturing with dasatinib facilitates higher CAR T-cell yield, improved fitness, and preserved functionality. In vivo, dasatinib can be used to temporarily and reversibly suppress CAR T-cell activity. With this supporting translational data, we are initiating a trial with low-affinity CD127 CAR T cells for adult and pediatric patients with relapsed or refractory T-ALL.

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (9) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. (16) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (17) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org. Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. adusumip@mskcc.org.

Citation: Nat Commun 2026 Jul 15 Epub07/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42457686

Tags:

In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum Spotlight 

(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X

Science advances | Free PMC Article

Wang et al. engineered an “all-in-one” cancer cell-derived vaccine (UniCVac) by co-expressing CIITA, NLRC5, CD80, and IL-2 in tumor cells to mimic professional APCs with both HLA-I and HLA-II antigen presentation, co-stimulation, and T cell growth signal. UniCVac cells presented antigens to both CD4+ and CD8+ T cells in vitro, driving activation and proliferation similar to APCs. UniCVac achieved potent antitumor activity in therapeutic (NSG) models, and induced polyclonal tumor-specific T cell responses, reprogrammed the immunosuppressive TIME to be immune-permissive, and enhanced tumor control in B16 and MC38 tumor models.

Contributed by Shishir Pant

(1) Wang W (2) Huang Y (3) Zhang J (4) Wang Y (5) Yu Z (6) Zhang F (7) Zhang H (8) Zhang R (9) Zhong R (10) Zhong H (11) Zhang L (12) Liu C (13) Shen C (14) Li Z (15) Wang M (16) Yang X

Science advances | Free PMC Article

Wang et al. engineered an “all-in-one” cancer cell-derived vaccine (UniCVac) by co-expressing CIITA, NLRC5, CD80, and IL-2 in tumor cells to mimic professional APCs with both HLA-I and HLA-II antigen presentation, co-stimulation, and T cell growth signal. UniCVac cells presented antigens to both CD4+ and CD8+ T cells in vitro, driving activation and proliferation similar to APCs. UniCVac achieved potent antitumor activity in therapeutic (NSG) models, and induced polyclonal tumor-specific T cell responses, reprogrammed the immunosuppressive TIME to be immune-permissive, and enhanced tumor control in B16 and MC38 tumor models.

Contributed by Shishir Pant

ABSTRACT: Cancer vaccines offer a promising strategy to initiate de novo T cell responses or enhance existing ones, either functioning independently or synergizing with T cell-modulating therapeutics to reduce tumor burden. The clinical development of cancer vaccines faces challenges such as limited antigen coverage, insufficient antigen presentation, immune suppressive microenvironment, and the availability of personalized vaccines. In this study, we developed a universal "all-in-one" cancer cell-derived vaccine (UniCVac) with comprehensive antigen spectrum coverage by programming tumor cells into antigen-presenting cells (APCs) through the codelivery of CIITA, NLRC5, CD80, and IL-2. This reprogramming mimics the professional APC phenotype, providing simultaneous HLA-I and HLA-II antigen presentation, costimulation, and T cell proliferation signals. These tumor-derived UniCVac can directly activate both CD4(+) and CD8(+) T cells in vitro, independent of APCs. In addition, their costimulation and T cell growth-stimulating capabilities result in superior CD4(+) and CD8(+) T cell activation and proliferation comparable to traditional APCs, with enhanced PI3K-AKT pathways activation. Single-cell transcriptome analysis confirmed the similarity in cellular subtypes between UniCVac-activated and traditional APC-activated T cells. In mouse models, the UniCVac vaccination reprogramed the tumor microenvironment from immunosuppressive to immune-permissive, induced robust CD4(+) and CD8(+) T cell expansion in both preventive and therapeutic tumor models, and achieved complete tumor regression in vivo. Our approach provides a platform for the development of universal cancer vaccines with full antigen spectrum coverage and the ability to directly activate both CD4(+) and CD8(+) T cells, offering potential combinatorial opportunities with existing T cell-based immunotherapies against cancer.

Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (2) Sheng Yushou Center of Cell B

Author Info: (1) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (2) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (3) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (4) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (5) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (6) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (7) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (8) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. (9) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (10) Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (11) Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Cellular and Molecular Medicine, School of life sciences, University of Bristol, Bristol, UK. (13) Department of mathematics and statistics, Northeastern University at Qinhuangdao, Qinhuangdao, China. (14) Department of Biomedical Sciences, University College London, London, UK. (15) Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. (16) Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Department of Gynaecology and Obstetrics, Shanghai Pudong New Area People's Hospital, Shanghai, China. Engineering Research Center of Cell & Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai, China.

Citation: Sci Adv 2026 Jul 10 12:eaee5201 Epub07/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42418568

Tags:

The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity Featured  

(1) Zhang X (2) Xirenayi S (3) Zhao Y (4) Wang W (5) Han Y (6) Sobral M (7) Kang S (8) Zhang C (9) Barlow GL (10) Pyrdol J (11) Cho JW (12) Huang K (13) Ning X (14) Hemberg M (15) Yuan GC (16) Van Allen EM (17) Mooney DJ (18) Wucherpfennig KW

Science

Zhang et al. investigated the role of the CARM1 in cDC1s and found that while its effect on cDC1s in healthy tissues was minimal, inactivation of Carm1 in tumor cDC1s enhanced their activation and cross-presentation of tumor antigens, resulting in increased CD8+ T cell-mediated antitumor efficacy. Carm1 expression was found to be downregulated by type 1 IFN and TNFα, and upregulated by TGFβ via Smad2/3. CARM1 altered chromatin expression, with its loss leading to enhanced chromatin access at regions associated with NF-κB and AP-1 binding, which supported enhanced activation and antigen presentation. When used in combination with a neoantigen vaccine, inhibition of Carm1 enhanced antitumor responses.

(1) Zhang X (2) Xirenayi S (3) Zhao Y (4) Wang W (5) Han Y (6) Sobral M (7) Kang S (8) Zhang C (9) Barlow GL (10) Pyrdol J (11) Cho JW (12) Huang K (13) Ning X (14) Hemberg M (15) Yuan GC (16) Van Allen EM (17) Mooney DJ (18) Wucherpfennig KW

Science

Zhang et al. investigated the role of the CARM1 in cDC1s and found that while its effect on cDC1s in healthy tissues was minimal, inactivation of Carm1 in tumor cDC1s enhanced their activation and cross-presentation of tumor antigens, resulting in increased CD8+ T cell-mediated antitumor efficacy. Carm1 expression was found to be downregulated by type 1 IFN and TNFα, and upregulated by TGFβ via Smad2/3. CARM1 altered chromatin expression, with its loss leading to enhanced chromatin access at regions associated with NF-κB and AP-1 binding, which supported enhanced activation and antigen presentation. When used in combination with a neoantigen vaccine, inhibition of Carm1 enhanced antitumor responses.

ABSTRACT: The cancer-immunity cycle requires cross-presenting type I conventional dendritic cells (cDC1s) that induce T cell-mediated immunity, but therapeutic strategies for enhancing intratumoral cDC1 function are currently inadequate. We found the epigenetic enzyme CARM1 (coactivator-associated arginine methyltransferase 1) to be a selective negative regulator of cancer antigen presentation by cDC1s but not cDC2s. Inactivation of the Carm1 gene promoted cDC1 antigen cross-presentation, activation, and accumulation in tumors, and a CARM1 inhibitor enhanced cDC1-mediated priming of T cells by means of a cancer neoantigen vaccine. CARM1 inhibition increased chromatin accessibility at BATF3-Jun and RelA sites that are critical for cDC1 function and activation. Transforming growth factor-β regulated Carm1 expression, which suggests that CARM1 inactivation enhanced intratumoral cDC1 function without altering cDC1 homeostasis. These studies identify CARM1 as a potential therapeutic target for enhancing the antitumor function of mouse and human cDC1s.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department o

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. Systems, Synthetic, and Quantitative Biology Graduate Program, Harvard University, Cambridge, MA, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (6) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. (7) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (12) Molecular Imaging Core, Dana-Farber Cancer Institute, Boston, MA, USA. (13) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. (14) Broad Institute of Harvard and MIT, Cambridge, MA, USA. Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (15) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Black Family Stem Cell Institute, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Immunology, Harvard Medical School, Boston, MA, USA. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.

Citation: Science 2026 Jul 9 393:eaea1200 Epub07/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42424445

Tags:

Enhancement of ferroptosis in escape variant tumor cells by IFN-γ derived from antigen-specific T cells controls tumor with heterogeneity

Spotlight 

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

(1) Ehara D (2) Yasui K (3) Yoneda M (4) Muraoka D (5) Deng S (6) Miao P (7) Jiang C (8) Sun H (9) Okamoto S (10) Amaishi Y (11) Murota H (12) Ikeda H

Cancer immunology research

To enhance immunotherapy efficacy against escape variant clones, Ehara et al. combined MART-1 TCR-T cells with the ferroptosis inducer RSL3. IFNγ secreted by the TCR-T cells enhanced the susceptibility of melanoma cells to ferroptosis. In mice injected with an equal mix of 526MEL and β2mKO cells, the combination treatment inhibited tumor growth, including reduction of the HLA-negative tumor mass, and significantly increased T cell infiltration compared to controls. In patients with melanoma, high expression of IFNγ signature genes STAT1 and IRF1 and low expression of SLC2A2 (counteracting ferroptosis) predicted better outcomes.

Contributed by Ute Burkhardt

ABSTRACT: Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFN-γ suppresses the expression of System Xc-, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1-specific TCR-T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2 microglobulin knockout counterparts. In NOG mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape variant tumor clones, offering a promising strategy for cancer treatment.

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan

Author Info: (1) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (2) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (3) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (4) Aichi Cancer Center Research Institute Chikusa-ku, Nagoya, Aichi Japan. (5) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (6) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (7) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (8) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (9) Takara Bio Inc. Kusatsu, Shiga Japan. (10) Takara Bio Inc. Otsu, Shiga Japan. (11) Nagasaki University Nagasaki Japan. ROR: https://ror.org/058h74p94 (12) Nagasaki University Nagasaki, Nagasaki Japan. ROR: https://ror.org/058h74p94

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397036

Tags:

Sustained A2AR expression and loss paradoxically promote CD8+ T cell exhaustion

Spotlight 

(1) Song L (2) Kharel A (3) Xie P (4) Fan J (5) Baker A (6) Zhang Y (7) Zhang Y (8) Cui W (9) Zhang B

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

Using single-cell multiomics and genetic models, Song and Kharel et al. showed that, paradoxically, both sustained A2AR expression under chronic antigen exposure and hypoxia, and complete loss of A2AR drive the transition of TCFhi memory-like progenitor (Tpro) cells to exhausted T cells. A2AR expression was rapidly induced upon TCR stimulation and was required to sustain CD8+ T cell functions. Persistent A2AR expression promoted continuous TCR engagement and CD8+ T cell exhaustion via activation of the GαS-cAMP-PKA pathway. A2AR depletion led to epigenetic remodeling and activation of CD122 (IL-2Rβ)-dependent signaling, driving exhaustion.

Contributed by Ute Burkhardt

(1) Song L (2) Kharel A (3) Xie P (4) Fan J (5) Baker A (6) Zhang Y (7) Zhang Y (8) Cui W (9) Zhang B

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

Using single-cell multiomics and genetic models, Song and Kharel et al. showed that, paradoxically, both sustained A2AR expression under chronic antigen exposure and hypoxia, and complete loss of A2AR drive the transition of TCFhi memory-like progenitor (Tpro) cells to exhausted T cells. A2AR expression was rapidly induced upon TCR stimulation and was required to sustain CD8+ T cell functions. Persistent A2AR expression promoted continuous TCR engagement and CD8+ T cell exhaustion via activation of the GαS-cAMP-PKA pathway. A2AR depletion led to epigenetic remodeling and activation of CD122 (IL-2Rβ)-dependent signaling, driving exhaustion.

Contributed by Ute Burkhardt

ABSTRACT: Although A2AR is a key immunoregulatory receptor that suppresses CD8(+) T cell activation in response to elevated extracellular adenosine in inflamed or hypoxic microenvironments, its role in CD8(+) T cell differentiation and cell-fate decisions during chronic viral infection and cancer remains poorly understood. Using A2AR-eGFP reporter mice, we show that A2AR expression is rapidly induced by TCR stimulation and persists under chronic antigen exposure and hypoxia, with sustained expression strongly associated with terminal exhaustion via the canonical G_(s)-cAMP-PKA pathway. Paradoxically, A2AR loss does not alleviate exhaustion but instead accelerates differentiation toward the terminally exhausted state. Single-cell multiomics profiling revealed that A2AR deficiency activates CD122 (IL-2R_)-dependent signaling, driving T cell exhaustion. Genetic deletion of CD122 in A2AR-deficient CD8(+) T cells reduced terminal exhaustion, identifying CD122 signaling as a key mediator of A2AR loss-driven exhaustion. Intriguingly, both sustained A2AR expression and A2AR loss converge to promote T cell exhaustion differentiation through distinct mechanisms. These findings uncover a paradoxical role of A2AR in shaping CD8(+) T cell fate choices during chronic infection and cancer.

Author Info: (1) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611.

Author Info: (1) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (2) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (3) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (4) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (5) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57 (6) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (7) Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. ROR: https://ror.org/056swr059 (8) Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611. (9) Department of Medicine and Hematology and Oncology Division, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine Chicago, IL 60611. ROR: https://ror.org/02p4far57

Citation: Proc Natl Acad Sci U S A 2026 Jul 7 123:e2602385123 Epub06/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42378284

Tags:

RIG-I-targeted immunotherapy synergizes with immune checkpoint inhibition in a hepatocellular carcinoma model Spotlight 

(1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

Molecular cancer therapeutics

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

(1) Marx C (2) Teppert J (3) Marisch L (4) Formisano S (5) Senz A (6) Boehmer DFR (7) Metzger P (8) Kechur D (9) Delius L (10) Hoerth C (11) Lauber K (12) Mayr D (13) De Toni EN (14) Helms MW (15) Brunner B (16) Endres S (17) Schnurr M (18) Duewell P (19) Rothenfusser S (20) Koenig LM

Molecular cancer therapeutics

Marx, Teppert, and Marisch et al. showed retinoic acid-inducible gene-I (RIG-I), the cytoplasmic sensor of short dsRNA with uncapped 5’-triphosphate (3p-RNA), was expressed in human HCC samples and induced by IFN-I on cell lines. 3p-RNA treatment given i.v. reduced tumor burden in murine orthotopic tumor models and induced immune memory. Therapeutic effects depended on CD4+ and CD8+ T, but not NK cells, and on tumor-intrinsic Fas expression, but not systemic intracellular RIG-I pathway signaling. Treatment with 3p-RNA upregulated PD-L1 expression on HCC cells and synergized with anti-PD-1 to improve efficacy in HCC mouse models.

Contributed by Paula Hochman

ABSTRACT: Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic pattern recognition receptor that senses short double-stranded RNA with uncapped 5'-triphosphate (3p-RNA). Upon activation, RIG-I induces type I interferons and proinflammatory cytokines, thereby promoting adaptive immunity. Thus, RIG-I activation is a promising approach for creating a proinflammatory tumor microenvironment. In this study, we investigated its therapeutic potential in hepatocellular carcinoma (HCC). We explored and confirmed RIG-I expression and signaling in human HCC samples and cell lines. The therapeutic potential of RIG-I activation by 3p-RNA for the treatment of HCC was investigated in vitro and in syngeneic murine orthotopic tumor models. In vivo, 3p-RNA treatment significantly reduced the tumor burden, delayed disease progression, and achieved partial complete remission of RIL-175 tumors with durable immune memory. However, no therapeutic effects were observed in the Hep-55.1C model. Tumor clearance depended on CD4⁺ and CD8⁺ T cells, but not NK cells. Additionally, 3p-RNA induced PD-L1 expression on HCC cells, enhancing their sensitivity to anti-PD-1 immune checkpoint therapy in vivo. RIG-I activation via 3p-RNA therapy shows promise as an immunotherapeutic strategy for hepatocellular carcinoma (HCC). Future investigations need to focus on tumor-intrinsic factors to understand heterogeneity between tumors and to overcome resistance mechanisms.

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.or

Author Info: (1) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (2) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (3) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (4) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (5) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (6) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (7) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (8) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (9) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (10) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (11) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (12) Ludwig-Maximilians-UniversitŠt MŸnchen Munich, Bavaria Germany. ROR: https://ror.org/05591te55 (13) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (14) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (15) Sanofi (Germany) Frankfurt Germany. ROR: https://ror.org/03ytdtb31 (16) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (17) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (18) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (19) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32 (20) LMU Klinikum Munich Germany. ROR: https://ror.org/02jet3w32

Citation: Mol Cancer Ther 2026 Jun 25 Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42345470

Tags:
Close Modal

Subscribe to our mailing list

GDPR Marketing Permissions

The Fritsch Foundation/ACIR.org will use the information you provide on this form to be in touch with you and to send you a weekly digest on cance immunotherapy. Click below to confirm that you want to receive the weekly digest by:

You can change your mind at any time by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at contact@acir.org. We will treat your information with respect and will never share it with any third-parties. By clicking below, you agree that we may process your information in accordance with these terms.

We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices here.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.