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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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

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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

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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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Addressing Biases in Analysis of Time of Infusion: NCI/SWOG Trial S1404 Among Participants With High-Risk Resectable Melanoma Who Received Adjuvant Anti-PD-1 Therapy Spotlight 

(1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

JCO oncology practice | Free PMC Article

In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

Contributed by Ute Burkhardt

(1) Othus M (2) Truong TG (3) Sharon E (4) Kendra K (5) Grossmann K (6) Buchbinder E (7) Khushalani NI (8) Eroglu Z (9) Chandra S (10) Doolittle GC (11) Kirkwood JM (12) Ikeguchi A (13) Mihalcioiu C (14) Cowey CL (15) Reddy SA (16) Johnson DB (17) Taylor M (18) Sondak VK (19) Ribas A (20) Patel SP

JCO oncology practice | Free PMC Article

In an analysis of a multi-center trial involving 628 patients with high-risk melanoma receiving adjuvant pembrolizumab, Othus et al. identified optimal time cut-points for the first infusion of 1:18 pm for recurrence-free survival and 3:48 pm for overall survival (OS). These findings, however, did not reach statistical significance regarding patient outcomes. Furthermore, the lack of threshold robustness was demonstrated when shifting the OS cut-point 30 minutes earlier, which yielded a hazard ratio of 0.98. Average infusion times trended earlier over the year, while appointments were on average later for patients living further from the treatment center.

Contributed by Ute Burkhardt

PURPOSE: Multiple reports have suggested that receiving immunotherapy infusions earlier in the day is associated with improved outcomes, including longer overall survival (OS) and lower toxicity rates. However, the definition of early varies between publications. Reports also fail to account for confounding factors (including distance to infusion center), are subject to survivor bias (analyzing postbaseline factors at baseline), and do not adjust P values for multiple comparisons when evaluating multiple potential thresholds for early versus late time of day of infusion. METHODS: We analyzed a previously reported multicenter clinical trial evaluating pembrolizumab as adjuvant therapy for participants with resectable high-risk melanoma. Standard statistical methodologies that account for potential biasses were used to evaluate the association between time of day of infusion and clinical outcomes. RESULTS: A total of 628 participants received pembrolizumab and had time of first infusion recorded. The median age was 55 years, range, 20-82. Odds of infusion before 11:00 hours increased by 32% over 12 months of therapy (P = .013). Participants living further from their treating institution had later infusion times on average: odds of infusion before 11:00 decreased by 9% for each additional 50 miles (P = .017). The optimal cut point for first infusion time for OS was 15:48 with hazard ratio (HR) = 1.40; changing the cut point by 30 minutes earlier to 15:18 decreased HR to 0.98, indicating lack of robustness of the threshold. No significant association was identified between proportion of early infusions and outcomes in multivariable time-dependent Cox regression models. CONCLUSION: In this multicenter trial of adjuvant pembrolizumab for participants with high-risk melanoma, analyses that account for common sources of bias found no significant association between recurrence-free or OS and time of day of infusion.

Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3)

Author Info: (1) Division of Public Health, Fred Hutchinson Cancer Center, Seattle WA. (2) Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. (3) Department of Medicine, Dana Farber Cancer Institute, Boston, MA. Harvard Medical School, Boston, MA. (4) Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH. (5) Medical Oncology, Providence Cancer Institute, Portland, OR. (6) Medical Oncology, Mass General Brigham Cancer Institute, Boston, MA. (7) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (8) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (9) Division of Hematology and Oncology, Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL. (10) Division of Clinical Oncology, University of Kansas Medical Center, Kansas City, KS. (11) Melanoma Program, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA. (12) Melanoma Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX. (13) Medical Oncology, McGill University Health Centre, Montreal, Canada. (14) Melanoma, Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX. (15) Department of Medical Oncology, Stanford University School of Medicine, Palo Alto, CA. (16) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. (17) Medical Oncology, Providence Cancer Institute, Portland, OR. (18) Department of Cutaneous Oncology, H Lee Moffitt Cancer Center, Tampa, FL. (19) Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA. (20) Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO.

Citation: JCO Oncol Pract 2026 Jun 23 OP2501413 Epub06/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42335437

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FLT3L-secreting cDC1 in situ vaccination enhances antitumor immunity and synergizes with PD-1 blockade in murine non-small cell lung cancer Spotlight 

(1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

Journal for immunotherapy of cancer | Free PMC Article

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

(1) Abascal J (2) Dumitras C (3) Tran LM (4) Crosson W (5) Kahangi B (6) Oh M (7) Rennels A (8) Lim RJ (9) Jiang H (10) Reyimjan D (11) Coleman NJ (12) Perez-Reyes E (13) Chin S (14) Krysan K (15) Dubinett SM (16) Liu B (17) Salehi-Rad R

Journal for immunotherapy of cancer | Free PMC Article

Abascal et al. engineered FLT3L-secreting mouse cDC1s that retained APC and phagocytic ability in vitro. In situ vaccination (ISV) with the cDC1s inhibited s.c. tumor growth in multiple syngeneic murine models, including those with driver mutations common in human NSCLC, and increased trafficking of the autologous cDC1s to TdLN and tumor infiltration of T cells. TCGA analysis showed that FLT3L expression in human NSCLC correlated with profiles of B and T cells, activated DCs and HEV-enriched TLS. ISV increased immature TLS formation in the murine TIME and synergized with anti-PD-1 in a NSCLC model to enhance efficacy and induce immune memory.

Contributed by Paula Hochman

BACKGROUND: Non-small cell lung cancer (NSCLC) frequently evades immune surveillance through defective antigen presentation and a suppressive tumor microenvironment (TME), limiting the efficacy of immune checkpoint blockade (ICB). Conventional type 1 dendritic cells (cDC1s) are essential for initiating antitumor CD8(+) T-cell responses; however, their abundance and function are often diminished in NSCLC, contributing to poor outcomes and resistance to immunotherapy. We hypothesized that in situ vaccination (ISV) using gene-modified cDC1s engineered to secrete FMS-like tyrosine kinase 3 ligand (FLT3L) would enhance cDC1 function within the TME, promote antitumor immunity, and improve responses to ICB. METHODS: Syngeneic murine models of NSCLC (Kras(G12D)/P53(-/-)/Lkb1(-/-); Kras(G12D)/P53(-/-) ; and Kras(G12D) ) with varying tumor mutational burden, along with the MC38 model, were used to assess the therapeutic efficacy of FLT3L-cDC1 ISV. Flow cytometry and multiplex immunofluorescence were used to evaluate immune mechanisms of response. To assess translational relevance, immune and tertiary lymphoid structure (TLS) signatures were analyzed in The Cancer Genome Atlas (TCGA) NSCLC datasets, with TLS signatures refined using a retrained xCell2 framework incorporating curated TLS and high endothelial venule (HEV) microdissection datasets. RESULTS: FLT3L-cDC1 ISV remodeled the TME across multiple NSCLC models, inducing T lymphocyte infiltration and expanding cytolytic CD8(+) T cells. FLT3L-cDC1 ISV was associated with increased formation of immature TLS with primary follicle-like features within the TME. TCGA analyses revealed that FLT3L expression correlates with activated DC, T cell, and B cell signatures, as well as HEV-enriched TLS-associated programs. Combination with PD-1 blockade further enhanced the antitumor immunity of FLT3L-cDC1 ISV, resulting in robust local and systemic T-cell activation and the expansion of activated CCR7(+)PD-L1(+) cDC1s and stem-like TCF1(+)PD-1(+) CD8(+) progenitors within the TME. In an LKB1-deficient NSCLC model, FLT3L-cDC1 ISV plus PD-1 blockade induced complete and durable regression in 85% of tumors, leading to long-lasting systemic tumor-specific immune memory, consistent with effective tumor vaccination. CONCLUSIONS: FLT3L-cDC1 ISV represents a rational cytokine-enhanced cellular immunotherapy designed to overcome immunosuppression and restore DC function within the TME, thereby promoting tumor-specific adaptive immune responses and enhancing responsiveness to ICB.

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA

Author Info: (1) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (2) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (3) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (4) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (5) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (6) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. (7) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (8) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (9) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (10) UCLA, Los Angeles, California, USA. (11) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (12) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (13) Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (14) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. (15) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, Los Angeles, California, USA. (16) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. (17) Department of Medicine, David Geffen School of Medicine, Los Angeles, California, USA rsalehirad@mednet.ucla.edu bliu@mednet.ucla.edu. VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.

Citation: J Immunother Cancer 2026 Jun 25 14: Epub06/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42350046

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A radiopharmaceutical enhances CAR T cells against radio-sensitive and radio-resistant neuroblastoma by tumor sensitization and TME remodeling Spotlight 

(1) Rodriguez C (2) Edinger RS (3) Diehl G (4) Reyes-Gonz‡lez JM (5) Lee W (6) Buckley J (7) Oh J (8) Nambiar D (9) Baidoo K (10) Okada R (11) Phadke I (12) Schmiechen Z (13) Khan H (14) Sakhalkar Y (15) Cortez AG (16) Josefsson A (17) Nedrow JR (18) White A (19) Citrin DE (20) Zhang X (21) Anderson CJ (22) Escorcia FE (23) Patel RB (24) Nguyen R

Cell reports. Medicine

Rodriguez and Edinger et al. showed that pre-treatment with VLA-4-targeted, low-dose radiopharmaceutical therapy (RPT) using [67Cu] Cu-LLP2A enhanced GD2 or B7-H3 CAR T cell efficacy, resulting in significant tumor regression in xenogeneic, preclinical neuroblastoma models. The mechanism of action varied with tumor radiosensitivity. In radiosensitive tumors, RPT was directly tumoricidal and enhanced CAR T cell efficacy via TNF-α, leading to paracrine T cell activation. In radioresistant tumors, RPT remodeled the TIME by decreasing the number of M2-like TAMs and stimulating the formation of enriched cytotoxic CD4+ and CD8+ T cell clusters.

Contributed by Katherine Turner

(1) Rodriguez C (2) Edinger RS (3) Diehl G (4) Reyes-Gonz‡lez JM (5) Lee W (6) Buckley J (7) Oh J (8) Nambiar D (9) Baidoo K (10) Okada R (11) Phadke I (12) Schmiechen Z (13) Khan H (14) Sakhalkar Y (15) Cortez AG (16) Josefsson A (17) Nedrow JR (18) White A (19) Citrin DE (20) Zhang X (21) Anderson CJ (22) Escorcia FE (23) Patel RB (24) Nguyen R

Cell reports. Medicine

Rodriguez and Edinger et al. showed that pre-treatment with VLA-4-targeted, low-dose radiopharmaceutical therapy (RPT) using [67Cu] Cu-LLP2A enhanced GD2 or B7-H3 CAR T cell efficacy, resulting in significant tumor regression in xenogeneic, preclinical neuroblastoma models. The mechanism of action varied with tumor radiosensitivity. In radiosensitive tumors, RPT was directly tumoricidal and enhanced CAR T cell efficacy via TNF-α, leading to paracrine T cell activation. In radioresistant tumors, RPT remodeled the TIME by decreasing the number of M2-like TAMs and stimulating the formation of enriched cytotoxic CD4+ and CD8+ T cell clusters.

Contributed by Katherine Turner

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has limited efficacy against solid tumors such as neuroblastoma (NB). Key obstacles include extensive tumor burden and the presence of an immunosuppressive tumor microenvironment (TME). We employ targeted radiopharmaceutical therapy (RPT) using [(67)Cu]Cu-LLP2A and show that it potentiated the anti-tumor activity of CAR T cells in radio-sensitive and radio-resistant NB models via distinct mechanisms. In radio-sensitive NB, RPT is directly tumoricidal while also enhancing CAR T cell efficacy through pro-immune pathways, most notably via the TNF-_ pathway, leading to paracrine activation of T cells. In radio-resistant NB, RPT improves CAR T cells by remodeling the myeloid compartment in the TME and increasing the formation of immunological niches of cytotoxic CD8(+) GZMB(+) and CD4(+) GZMB(+) CAR T cells. While neither treatment modality alone can effectively treat NB, the combination of VLA-4-targeted RPT and GD2 or B7-H3 CAR T cells augments anti-tumor efficacy, resulting in marked tumor regression in preclinical NB models.

Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, Univer

Author Info: (1) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (2) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (3) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (4) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (5) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (6) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (7) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (8) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (9) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (10) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (11) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (12) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (13) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. (14) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (15) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (16) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (17) Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. (18) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (19) Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. (20) Rutgers Cancer Institute, New Brunswick, NJ, USA; Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA. (21) Departments of Chemistry and Radiology, University of Missouri, Columbia, MO, USA. (22) Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: freddy.escorcia@gmail.com. (23) Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA; Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Biomedical Engineering, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: patelr20@upmc.edu. (24) Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: hongharosa.nguyen@nih.gov.

Citation: Cell Rep Med 2026 Jun 23 102884 Epub06/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42335901

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Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer Spotlight 

(1) Adler KM (2) Xu H (3) Gladstein AC (4) Irizarry-Negron VM (5) Robertson MR (6) Doerig KR (7) Petrov DA (8) Winslow MM (9) Feldser DM

Nature communications

Using genetically engineered conditional mouse models and lentiviral-mediated somatic gene inactivation, Adler and Xu et al. developed models that allowed them to quantify immunoediting by evaluating fixed neoantigen expression against genotypic tumor backgrounds defined by common driver mutations and different tumor suppressor genes. While genetic features promoting tumor proliferation generally correlated with increased sensitivity to immunosurveillance, different genotypes differentially affected immune cell recruitment, selection of tumor cells with neoantigen silencing, tumor growth, and mechanisms of immune evasion.

Contributed by Lauren Hitchings

(1) Adler KM (2) Xu H (3) Gladstein AC (4) Irizarry-Negron VM (5) Robertson MR (6) Doerig KR (7) Petrov DA (8) Winslow MM (9) Feldser DM

Nature communications

Using genetically engineered conditional mouse models and lentiviral-mediated somatic gene inactivation, Adler and Xu et al. developed models that allowed them to quantify immunoediting by evaluating fixed neoantigen expression against genotypic tumor backgrounds defined by common driver mutations and different tumor suppressor genes. While genetic features promoting tumor proliferation generally correlated with increased sensitivity to immunosurveillance, different genotypes differentially affected immune cell recruitment, selection of tumor cells with neoantigen silencing, tumor growth, and mechanisms of immune evasion.

Contributed by Lauren Hitchings

ABSTRACT: The impact of cancer driving mutations on immunosurveillance throughout tumor development remains poorly understood. To better understand the contribution of tumor genotype to immunosurveillance, we generated and validated lentiviral-based vectors that create increasingly immunogenic neoantigens. This vector system is compatible with autochthonous Cre-regulated cancer models, CRISPR/Cas9-mediated somatic genome editing, and tumor barcoding. Here, we show that in the context of oncogenic KRAS-driven lung cancer and strong neoantigen expression, tumor suppressor genotype dictates the degree of immune cell recruitment, positive selection of tumors with neoantigen silencing, and tumor outgrowth. By quantifying the impact of 11 commonly inactivated tumor suppressor genes on tumor growth across neoantigenic contexts, we show that the growth-promoting effects of tumor suppressor gene inactivation correlate with increasing sensitivity to immunosurveillance. Importantly, some genotypes also dramatically changed sensitivity to immunosurveillance independently of their growth-promoting effects. We propose a model of immunoediting in which tumor suppressor gene inactivation works in tandem with neoantigen expression to shape tumor immunosurveillance and immunoediting such that the same neoantigens uniquely modulate tumor immunoediting depending on the genetic context.

Author Info: (1) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medi

Author Info: (1) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. Department of Biology, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Biology, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu. Department of Biology, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. mwinslow@stanford.edu. (9) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu. Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. dfeldser@upenn.edu.

Citation: Nat Commun 2026 Jun 15 Epub06/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42297823

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An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function Spotlight 

(1) Min IM (2) Yang Y (3) Stefanova D (4) Vedvyas Y (5) Babu DS (6) Lee DH (7) Alcaina Y (8) Riascos MC (9) Puc J (10) Chen KJ (11) Gonzalez-Valdivieso J (12) Thaiparambil J (13) Bilal M (14) He B (15) Burnett AC (16) Zarnegar R (17) Fahey TJ (18) Jin MM

Cancer immunology research

Min et al. developed an ICAM1-specific 4-1BB fusion protein. Engagement of this chimeric costimulatory receptor (ICCR) enhanced tumor cell conjugation and force-dependent immune synapse stability, triggered NF-κB-signaling, and amplified TCR-driven functional activation of engineered T cells, particularly against targets with lower antigen density. In a patient-derived orthotropic xenograft model of aggressive, incurable thyroid cancer, autologous ICCR+ T cells showed selective expansion and prolongation of survival. ICCR+ T cells exhibited reduced TCR diversity, and upregulation of cytotoxicity, TCR signaling, costimulation, and exhaustion genes.

Contributed by Ute Burkhardt

(1) Min IM (2) Yang Y (3) Stefanova D (4) Vedvyas Y (5) Babu DS (6) Lee DH (7) Alcaina Y (8) Riascos MC (9) Puc J (10) Chen KJ (11) Gonzalez-Valdivieso J (12) Thaiparambil J (13) Bilal M (14) He B (15) Burnett AC (16) Zarnegar R (17) Fahey TJ (18) Jin MM

Cancer immunology research

Min et al. developed an ICAM1-specific 4-1BB fusion protein. Engagement of this chimeric costimulatory receptor (ICCR) enhanced tumor cell conjugation and force-dependent immune synapse stability, triggered NF-κB-signaling, and amplified TCR-driven functional activation of engineered T cells, particularly against targets with lower antigen density. In a patient-derived orthotropic xenograft model of aggressive, incurable thyroid cancer, autologous ICCR+ T cells showed selective expansion and prolongation of survival. ICCR+ T cells exhibited reduced TCR diversity, and upregulation of cytotoxicity, TCR signaling, costimulation, and exhaustion genes.

Contributed by Ute Burkhardt

ABSTRACT: Engineered T cell therapies, such as chimeric antigen receptor (CAR) and T cell receptor (TCR)-based approaches, have transformed outcomes in hematological malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFN_ released during early T cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NF_B signaling independently of TCR-p/MHC engagement; however, full T cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T cell responses in solid tumor microenvironments.

Author Info: (1) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (2) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (3) Weill Corn

Author Info: (1) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (2) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (3) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (4) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (5) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (6) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (7) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (8) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (9) AffyImmune Therapeutics, Inc. Natick, MA United States. (10) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (11) Weill Cornell Medicine New York, NY United States. ROR: https://ror.org/02r109517 (12) Houston Methodist Research Institute Houston, TX United States. (13) Weill Cornell Medicine New York, New York United States. ROR: https://ror.org/02r109517 (14) Weill Cornell Medicine New York, New York United States. ROR: https://ror.org/02r109517 (15) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171 (16) New York Presbyterian Hospital - Weill Cornell Medical College New York, NY United States. (17) Weill Cornell New York, NY United States. (18) Houston Methodist Houston, TX United States. ROR: https://ror.org/027zt9171

Citation: Cancer Immunol Res 2026 Apr 27 Epub04/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42043451

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