Journal Articles

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

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CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors Spotlight 

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

(1) Lelliott EJ (2) Naddaf J (3) Lu KH (4) Cummins KD (5) Ramsbottom KM (6) Reynolds DS (7) Taylor M (8) Ambani K (9) Munoz I (10) Jackson S (11) Li J (12) Chan CW (13) Britt KL (14) Beavis PA (15) Goel S (16) Oliaro J

Molecular therapy | Free PMC Article

Lelliott et al. showed that the CDK4/6 inhibitor trilaciclib enhanced the metabolic fitness of and cytotoxicity by human CD19 CAR-T cells while reducing their proliferation in vitro. In mice with RB-proficient, trilaciclib-sensitive, CD19+ leukemia, trilaciclib plus CD19 CAR-T cell therapy was more efficacious than monotherapies. In mouse models of solid (breast, ovarian) tumors, even tumors poorly sensitive to trilaciclib alone responded better to tumor antigen-directed CAR-T cells plus trilaciclib than to the single therapies. Trilaciclib reduced suppressive Treg numbers and boosted CAR-T cell persistence, tumor trafficking, and cytotoxic function per cell in solid tumors.

Contributed by Paula Hochman

ABSTRACT: CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VI

Author Info: (1) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: emily.lelliott@petermac.org. (2) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (3) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (4) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (5) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (8) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (10) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (11) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (12) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (13) Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (15) Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: shom.goel@petermac.org. (16) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: jane.oliaro@petermac.org.

Citation: Mol Ther 2026 Jul 1 34:4021-4034 Epub03/24/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41883164

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An in vivo CRISPR screen unveils promising target genes to improve CAR-T cell efficacy in a solid tumor model Spotlight 

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

(1) Fumagalli M (2) An D (3) Simula L (4) Combe C (5) Aziez L (6) Simoni Y (7) Alves-Guerra MC (8) Valentini A (9) Marchais M (10) Vermare A (11) Moraly J (12) Manni S (13) Quadraccia MC (14) Quintarelli C (15) De Angelis B (16) Bercovici N (17) Donnadieu E (18) Pendino F

Molecular therapy | Free PMC Article

Fumagalli et al. developed a focused CRISPR-knockout library targeting loss-of-function of 50 relevant genes to screen low-affinity EGFR CAR-T cells in an orthotopic human lung adenocarcinoma (A549) model. In vivo screening identified ZC3H12A, SOCS1, PTPN2, and CDKN2A loss as top hits that enhanced CAR-T persistence and expansion, whereas MED12, PRDM1, or BATF loss impaired long-term efficacy. Targeted validation of ZC3H12A- and PTPN2-deficient CAR-T cells confirmed improved tumor control and survival. Gene-edited CAR-T cells showed versatility and tumor context specificity, and retained iCasp9 suicide switch activity.

Contributed by Shishir Pant

ABSTRACT: CAR-T cell therapies are revolutionizing the treatment of refractory or relapsed hematological malignancies, but many patients do not achieve durable responses, and these therapies remain ineffective against solid tumors. Therapeutic failure is closely associated with a poor persistence of CAR-T cells in patients, highlighting the need to identify strategies promoting in vivo expansion. Although numerous gene-editing strategies have been proposed, comparative studies to identify the most effective ones are still lacking. Here, using a focused CRISPR-knockout library targeting 50 selected gene candidates, we developed a competitive screening that revealed ZC3H12A, SOCS1, PTPN2, and CDKN2A as the most robust targets to improve persistence of EGFR CAR-T cells in human lung tumor-bearing mice. Surprisingly, disruption of other genes previously reported to improve CAR-T cell efficacy in other preclinical models-MED12, PRDM1, and BATF-had a detrimental effect in this context. These results suggest that some gene-editing strategies can yield beneficial, neutral, or even deleterious effects on CAR-T cell persistence, depending on specific conditions. Altogether, these findings highlight the importance of performing context-specific evaluations of genetic modifications to accelerate the clinical translation of the most promising editing strategies for optimizing CAR-T cell therapies.

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationa

Author Info: (1) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France; Thèse Financée par la Ligue Nationale Contre le Cancer, Paris, France. Electronic address: fumatia97@gmail.com. (2) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (3) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (4) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (5) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (6) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (7) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (8) Technical University of Denmark, 2800 Kongens Lyngby, Denmark. (9) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France. (10) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (11) Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. (12) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (13) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (14) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, 80131 Naples, Italy. (15) Department of Onco-Haematology and Cell and Gene Therapy, Bambino Ges Children's Hospital, IRCCS, 00165 Rome, Italy. (16) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (17) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. (18) Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014 Paris, France; Equipe Labélisée Ligue Nationale Contre le Cancer, Paris, France. Electronic address: frederic.pendino@inserm.fr.

Citation: Mol Ther 2026 Jul 1 34:3976-4000 Epub04/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41935953

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The critical role of the endogenous immune compartment after CAR T cell therapy in recurrent GBM Spotlight 

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

(1) Freeburg NF (2) Chafamo D (3) Konanur Gopikrishna G (4) Murphy RM (5) Peng JJ (6) Parthasarathy S (7) Dumont S (8) Estrada EG (9) Logun MT (10) Sun Y (11) Wang X (12) Grover P (13) Rodriguez JL (14) Zhang DL (15) Park K (16) Fu Y (17) Ben Hamouda N (18) Hernandez-Verdin I (19) Lamrani L (20) Hicks KA (21) Cooper NA (22) Ekwegbara C (23) Bawden EG (24) Waterfall JJ (25) Fuentealba J (26) Alcantara M (27) Seykora JT (28) Prouty SM (29) Barrett D (30) Banerjee E (31) Cox A (32) Assenmacher CA (33) Macia C (34) Yin M (35) Carpenter EL (36) Ming GL (37) Sauts-Fridman C (38) Fridman WH (39) Tartour E (40) Wherry EJ (41) Amigorena S (42) Fraietta JA (43) Nasrallah MP (44) Song H (45) Miller TE (46) Bagley SJ (47) O'Rourke DM (48) Binder ZA (49) Alanio C (50) Silverbush D

Cell

Freeburg and Chafamo et al. performed longitudinal single-cell profiling of CSF and tumors from 18 patients with recurrent GBM treated with a single intracerebroventricular dose of bivalent EGFR-IL13Rα2 CAR T cells. CAR T cells peaked at 7 days and showed increased cytotoxicity and exhaustion in CSF. Endogenous cytotoxic NK cells, Tregs, and “scavenger” myeloid cells also increased dose-dependently. Responses correlated with increased CD56dimCD16+ NK cells, while Treg expansion and a high baseline number of immunosuppressive myeloid cells correlated with non-response, emphasizing the endogenous immune system’s role in CAR T cell efficacy.

Contributed by Katherine Turner

ABSTRACT: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase 1 trial of intracerebroventricular bivalent chimeric antigen receptor (CAR) T cells in recurrent GBM, registered at ClinicalTrials.gov (NCT05168423), showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal cerebrospinal fluid (CSF) and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that, although CAR T cells activate post infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic natural killer cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive scavenger myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicin

Author Info: (1) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (2) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (3) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (5) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (6) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (7) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA. (9) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (10) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (13) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (14) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (15) Neuroscience Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (17) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (18) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France. (19) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (20) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (21) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (22) Clinical Immunology Laboratory, Institut Curie, Paris, France. (23) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (24) Department of Translational Research, PSL University, Institut Curie, Paris, France; INSERM U1330, PSL University, Institut Curie Research Center, Paris, France. (25) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France. (26) CellAction, Center for Cancer Immunotherapy, INSERM U932, Institut Curie, Saint-Cloud, France; Clinical Hematology Unit, Institut Curie, Saint-Cloud, France. (27) Departments of Dermatology and Pathology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (29) Kite, a Gilead Company, Santa Monica, CA, USA. (30) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (31) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (32) Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, School of Veterinary Medicine, Philadelphia, PA, USA. (33) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (34) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (35) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. (37) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (38) Centre de Recherche des Cordeliers, Sorbonne UniversitŽ, INSERM, UniversitŽ Paris CitŽ, 75006 Paris, France; ƒquipe labellisŽe Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 15 rue de l'Žcole de mŽdecine, 75006 Paris, France. (39) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Department of Immunology, APHP, H™pital EuropŽen Georges Pompidou (HEGP)-H™pital Necker, Paris, France. (40) Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology and Immune Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (41) Institut Curie, PSL University, INSERM U932, Immunity and Cancer, 75005 Paris, France. (42) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (43) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (44) Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (45) Department of Pathology, Case Western Reserve University School of Medicine and Case Comprehensive Cancer Center, Cleveland, OH, USA; Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (46) GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (47) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (48) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: binderz@pennmedicine.upenn.edu. (49) Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France; Clinical Laboratory, H™pital Foch, Suresnes, France. Electronic address: c.alanio@hopital-foch.com. (50) Cancer Biology Department, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dana.silverbush@pennmedicine.upenn.edu.

Citation: Cell 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42296961

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

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

Cancer immunology research

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

Contributed by Katherine Turner

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

Cancer immunology research

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

Contributed by Katherine Turner

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

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

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

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

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

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

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

Nature communications

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

Contributed by Alex Najibi

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

Nature communications

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

Contributed by Alex Najibi

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

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

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

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

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

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In vivo CAR T cell generation using retargeted and functionalized lentiviral vectors with reduced immunogenicity Spotlight 

(1) Ibrahim KE (2) Mears KS (3) Allen PM (4) Chinai JM (5) Avila OI (6) Muscato AJ (7) Lane-Reticker SK (8) Rojas A (9) Knudsen NH (10) Chao CC (11) Yates KB (12) Manguso RT

Nature communications

Measles virus (MeV) recognizes and fuses with target cells via hemagglutinin (H) and fusion (F) proteins, respectively. To achieve T cell-specific transduction, Ibrahim et al. produced a lentivirus (LV) expressing MEV-F and a re-targeted MEV-H linked to a targeting molecule (VHHs resulted in higher functional titers than scFvs). To avoid serum neutralization by anti-MeV antibodies, MeV-H/F proteins were redesigned as chimeras with dolphin morbillivirus-H/F. LVs expressing the chimeric proteins, CD7-targeting VHH, and anti-CD3 and CD80 (activation cues) generated CD19 CAR T cells in vivo and slowed Nalm6 tumor growth. CAR expression was largely restricted to T cells.

Contributed by Alex Najibi

(1) Ibrahim KE (2) Mears KS (3) Allen PM (4) Chinai JM (5) Avila OI (6) Muscato AJ (7) Lane-Reticker SK (8) Rojas A (9) Knudsen NH (10) Chao CC (11) Yates KB (12) Manguso RT

Nature communications

Measles virus (MeV) recognizes and fuses with target cells via hemagglutinin (H) and fusion (F) proteins, respectively. To achieve T cell-specific transduction, Ibrahim et al. produced a lentivirus (LV) expressing MEV-F and a re-targeted MEV-H linked to a targeting molecule (VHHs resulted in higher functional titers than scFvs). To avoid serum neutralization by anti-MeV antibodies, MeV-H/F proteins were redesigned as chimeras with dolphin morbillivirus-H/F. LVs expressing the chimeric proteins, CD7-targeting VHH, and anti-CD3 and CD80 (activation cues) generated CD19 CAR T cells in vivo and slowed Nalm6 tumor growth. CAR expression was largely restricted to T cells.

Contributed by Alex Najibi

ABSTRACT: Despite striking efficacy against hematologic malignancies, the cost and complexity of CAR T manufacturing present significant barriers to broader patient access. Beyond manufacturing challenges, ex vivo expansion of T cells may be detrimental to their function and persistence. Thus, delivery of CARs to reprogram host cells in vivo would represent a significant advance towards a readily available therapy, but has been limited by low efficiency, low specificity, and immunogenicity of viral vectors. Here, we describe the design of pseudotyped lentiviral vectors (LV) with superior functionality and high target specificity. We show that LV pseudotyped with chimeric envelope glycoproteins from dolphin morbillivirus (DMV) can be engineered to selectively infect human T cells and evade neutralizing antibody responses in measles-vaccinated human serum. We further demonstrate that camelid-derived nanobodies are a superior retargeting domain, overcoming limitations inherent to the use of single-chain variable fragment antibodies. Using a chimeric DMV-pseudotyped virus targeting the CD7 receptor, we demonstrate efficient and highly specific infection of T cells both in vitro and in vivo, generating functional CAR T cells and inducing therapeutic efficacy in a preclinical B cell lymphoma model.

Author Info: (1) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts Gen

Author Info: (1) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (2) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (3) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (4) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Dana-Farber Cancer Institute, Gastrointestinal Cancer Center, Boston, MA, USA. (5) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (6) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (7) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (8) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (9) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (10) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (11) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. yates@broadinstitute.org. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. yates@broadinstitute.org. (12) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. rmanguso@broadinstitute.org. Krantz Family Center for Cancer Research and Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. rmanguso@broadinstitute.org.

Citation: Nat Commun 2026 Apr 6 Epub04/06/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41942453

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Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models

Spotlight 

(1) Figueroa D (2) Vega JP (3) Hernández-Oliveras A (4) Ardiles F (5) Hidalgo S (6) López X (7) Saavedra V (8) Bustamante C (9) Malavó D (10) Flores F (11) Gálvez-Cancino F (12) Gonzalez H (13) Varas-Godoy M (14) Bono MR (15) Osorio F (16) Borgna V (17) Lladser A

Nature communications

Figueroa et al. demonstrated that lasting efficacy of adoptive T cell therapy (ACT) against solid tumors relied not only on the antitumor activity of transferred T cells, but also on their ability to expand host CD8+ T cells in a TNF- and cDC1-dependent manner. Host CD8+ T cells protected against rechallenge with ACT-resistant antigen-negative tumor cells. Lymphodepleting preconditioning promoted transferred T cell expansion, but impaired host immunity against antigen-loss variants. In patients with melanoma, enrichment of cDC1, TNF signaling, Tpex and Tex gene signatures correlated with clinical responses to ACT and better overall survival.

Contributed by Ute Burkhardt

(1) Figueroa D (2) Vega JP (3) Hernández-Oliveras A (4) Ardiles F (5) Hidalgo S (6) López X (7) Saavedra V (8) Bustamante C (9) Malavó D (10) Flores F (11) Gálvez-Cancino F (12) Gonzalez H (13) Varas-Godoy M (14) Bono MR (15) Osorio F (16) Borgna V (17) Lladser A

Nature communications

Figueroa et al. demonstrated that lasting efficacy of adoptive T cell therapy (ACT) against solid tumors relied not only on the antitumor activity of transferred T cells, but also on their ability to expand host CD8+ T cells in a TNF- and cDC1-dependent manner. Host CD8+ T cells protected against rechallenge with ACT-resistant antigen-negative tumor cells. Lymphodepleting preconditioning promoted transferred T cell expansion, but impaired host immunity against antigen-loss variants. In patients with melanoma, enrichment of cDC1, TNF signaling, Tpex and Tex gene signatures correlated with clinical responses to ACT and better overall survival.

Contributed by Ute Burkhardt

ABSTRACT: Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8(+) T cells that eradicate established murine tumors promote expansion of host CD8(+) T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8(+) T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8(+) T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8(+) T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.

Author Info: (1) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & V

Author Info: (1) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (2) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (3) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Investigaci—n e Innovaci—n en C‡ncer, Fundaci—n Arturo L—pez PŽrez OECI Cancer Center, Santiago, Chile. (4) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (5) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Investigaci—n e Innovaci—n en C‡ncer, Fundaci—n Arturo L—pez PŽrez OECI Cancer Center, Santiago, Chile. (6) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (7) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (8) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (9) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. (10) Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (11) Laboratory of Immune Regulation, NDM Centre for Immuno-Oncology, University of Oxford, Oxford, UK. (12) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. (13) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Centro de Biolog’a Celular y Biomedicina (CEBICEM), Facultad de Ciencias, Universidad San Sebasti‡n, Santiago, Chile. (14) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Laboratory of Immunology, Facultad de Ciencias, Universidad de Chile, Santiago, Chile. (15) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. Laboratory of Immunology and Cellular Stress, Facultad de Medicina, Universidad de Chile, Santiago, Chile. (16) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. vincenzo.borgna@uss.cl. Servicio de Urolog’a, Hospital Barros Luco Trudeau, Santiago, Chile. vincenzo.borgna@uss.cl. Facultad de Medicina, Universidad San Sebasti‡n, Santiago, Chile. vincenzo.borgna@uss.cl. (17) Centro Basal Ciencia & Vida, Fundaci—n Ciencia & Vida, Santiago, Chile. alladser@cienciavida.org. Facultad de Medicina, Universidad San Sebasti‡n, Santiago, Chile. alladser@cienciavida.org.

Citation: Nat Commun 2026 Mar 31 Epub03/31/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41912536

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In vivo generation of CAR myeloid cells through erythrocyte-mediated mRNA delivery for cancer immunotherapy Spotlight 

(1) Nie X (2) Liu Y (3) Song Y (4) Yao X (5) Chen Y (6) Lee HY (7) Gao X

Science translational medicine

Nie, Liu, Song, and Yao et al. developed a spleen delivery platform of mRNA-loaded lipid nanoparticles (LNPs) covalently bound to erythrocytes (mRNA-LNP-Ery), which naturally target splenic CD11b+ myeloid cells. Unlike conventional LNPs, mRNA-LNP-Ery entered cells via phagocytosis, avoiding lysosomal degradation and efficiently delivering mRNA. CAR myeloid cells (HER2 or CD19) adopted a proinflammatory antigen-presenting phenotype, migrated to tumors, and stimulated T and NK cell influx, potent antitumor activity, and systemic immunity, which was spleen-dependent. Repeated doses of mRNA-LNP-Ery resulted in superior efficacy at 1/10 the dose of LNPs.

Contributed by Katherine Turner

(1) Nie X (2) Liu Y (3) Song Y (4) Yao X (5) Chen Y (6) Lee HY (7) Gao X

Science translational medicine

Nie, Liu, Song, and Yao et al. developed a spleen delivery platform of mRNA-loaded lipid nanoparticles (LNPs) covalently bound to erythrocytes (mRNA-LNP-Ery), which naturally target splenic CD11b+ myeloid cells. Unlike conventional LNPs, mRNA-LNP-Ery entered cells via phagocytosis, avoiding lysosomal degradation and efficiently delivering mRNA. CAR myeloid cells (HER2 or CD19) adopted a proinflammatory antigen-presenting phenotype, migrated to tumors, and stimulated T and NK cell influx, potent antitumor activity, and systemic immunity, which was spleen-dependent. Repeated doses of mRNA-LNP-Ery resulted in superior efficacy at 1/10 the dose of LNPs.

Contributed by Katherine Turner

ABSTRACT: Engineering myeloid cells with chimeric antigen receptors (CARs) holds great therapeutic promise, but their generation in vivo remains challenging. Here, we developed an erythrocyte-mediated messenger RNA (mRNA) delivery platform, termed mRNA-LNP-Ery, in which mRNA-loaded lipid nanoparticles (LNPs) are covalently anchored onto erythrocytes. Exploiting erythrocytes' intrinsic splenic homing capacity and unique biocompatibility, mRNA-LNP-Ery enables highly selective and efficient mRNA delivery to CD11b(+) myeloid cells in the spleen, with minimal uptake by hepatocytes. We also demonstrated that mRNA-LNP-Ery is internalized through phagocytosis and avoids lysosomal degradation, resulting in enhanced cytosolic mRNA translation. Delivery of mRNAs encoding CARs targeting human epidermal growth factor receptor 2 (HER2) or CD19 generated functional CAR myeloid cells in vivo that adopted a proinflammatory, antigen-presenting phenotype. These cells migrated to tumors, eliminated cancer cells, and remodeled the tumor microenvironment, leading to increased infiltration of effector T and natural killer (NK) cells. The antitumor effect was abolished in splenectomized mice and partially diminished in nude mice, indicating that therapeutic activity depends on both CAR myeloid cell formation within the spleen and their cross-talk with adaptive immunity. Furthermore, repeated administration of mRNA-LNP-Ery achieved superior antitumor efficacy to conventional mRNA-LNPs at one-tenth the mRNA dose, with minimal systemic toxicity, underscoring the high efficiency and safety of spleen-targeted delivery. Together, our findings established a clinically translatable erythrocyte-based mRNA platform that enables direct in vivo immune cell programming and advances CAR myeloid therapies for solid tumors.

Author Info: (1) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake La

Author Info: (1) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. (2) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Research Center for Industries of the Future and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. (3) Westlake Therapeutics, Hangzhou, Zhejiang 310024, China. (4) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. (5) Westlake Therapeutics, Hangzhou, Zhejiang 310024, China. (6) Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China. (7) Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China. Research Center for Industries of the Future and School of Life Sciences, Westlake University, Hangzhou, Zhejiang 310030, China.

Citation: Sci Transl Med 2026 Mar 25 18:eady6730 Epub03/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41880522

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Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering Spotlight 

(1) Chen X (2) Mao Z (3) Kolawole EM (4) Persechino M (5) Jude KM (6) Ogishi M (7) Mo KC (8) McLaughlin J (9) Cheng D (10) Xiang X (11) Yang X (12) Gee C (13) Liu S (14) Yang A (15) Obenaus M (16) Wang N (17) Noguchi M (18) Stoyanova T (19) Lee JK (20) Good Z (21) Latorraca NR (22) Evavold BD (23) Witte ON (24) Garcia KC

Science | Free PMC Article

To improve the potency of a prostate TAA-specific TCR, Chen and Mao et al. screened for CDR hotspot mutations that could increase catch-bond formation and thus TCR sensitivity, without modifying TCR affinity (and the potential for off-target toxicity). Several variants increased TCR–pHLA bond lifetime, which correlated with TCR response to cognate peptide. These variants increased T cell proliferation, cytotoxicity, in vivo tumor efficacy, and effector/proliferative gene expression among TILs. Crystal structures and in silico modeling revealed alterations to water inclusion and hydrogen-bonding, supporting HLA, TCR, or peptide interactions.

Contributed by Alex Najibi

(1) Chen X (2) Mao Z (3) Kolawole EM (4) Persechino M (5) Jude KM (6) Ogishi M (7) Mo KC (8) McLaughlin J (9) Cheng D (10) Xiang X (11) Yang X (12) Gee C (13) Liu S (14) Yang A (15) Obenaus M (16) Wang N (17) Noguchi M (18) Stoyanova T (19) Lee JK (20) Good Z (21) Latorraca NR (22) Evavold BD (23) Witte ON (24) Garcia KC

Science | Free PMC Article

To improve the potency of a prostate TAA-specific TCR, Chen and Mao et al. screened for CDR hotspot mutations that could increase catch-bond formation and thus TCR sensitivity, without modifying TCR affinity (and the potential for off-target toxicity). Several variants increased TCR–pHLA bond lifetime, which correlated with TCR response to cognate peptide. These variants increased T cell proliferation, cytotoxicity, in vivo tumor efficacy, and effector/proliferative gene expression among TILs. Crystal structures and in silico modeling revealed alterations to water inclusion and hydrogen-bonding, supporting HLA, TCR, or peptide interactions.

Contributed by Alex Najibi

ABSTRACT: T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics,

Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (3) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (4) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (9) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (10) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (13) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (14) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (16) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (17) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (18) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Urology, UCLA, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (20) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. (21) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (22) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (23) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Molecular Biology Institute, UCLA, Los Angeles, CA, USA. (24) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.

Citation: Science 2026 Mar 19 391:eadx3162 Epub03/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855322

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