Journal Articles

In vivo engineering of CAR natural killer cells for immunotherapy using ligand-directed lipid nanoparticles Spotlight 

(1) Chen Y (2) Monkovic J (3) Mughal H (4) Chen B (5) Thadhani E (6) McMullen P (7) Self A (8) Chen Y (9) Hu Y (10) Detmer S (11) Chen M (12) Lapteva A (13) Kamat R (14) Vernon A (15) Langer R (16) Anderson DG

Nature biotechnology

Chen, Monkovic, and Mughal et al. used NK cell receptor-specific scFvs to generate NK cell-targeted LNPs (NtLNPs) that transfected up to 80% of circulating and tissue NK cells, with minimal off-target effects. NtLNP delivery of CAR mRNAs generated NK cells that specifically depleted B cells in healthy mice, restored AST/ALT to baseline levels in an autoimmune hepatitis model, and cleared antigen+ melanoma cells in a solid tumor model. NtLNPs targeting NKG2a boosted efficacy in solid tumor models by mitigating Qa-1b mediated immunosuppression. In vivo and ex vivo, NtLNP-generated human CAR NK cells induced regression in humanized lymphoma and T cell leukemia mouse models.

Contributed by Paula Hochman

(1) Chen Y (2) Monkovic J (3) Mughal H (4) Chen B (5) Thadhani E (6) McMullen P (7) Self A (8) Chen Y (9) Hu Y (10) Detmer S (11) Chen M (12) Lapteva A (13) Kamat R (14) Vernon A (15) Langer R (16) Anderson DG

Nature biotechnology

Chen, Monkovic, and Mughal et al. used NK cell receptor-specific scFvs to generate NK cell-targeted LNPs (NtLNPs) that transfected up to 80% of circulating and tissue NK cells, with minimal off-target effects. NtLNP delivery of CAR mRNAs generated NK cells that specifically depleted B cells in healthy mice, restored AST/ALT to baseline levels in an autoimmune hepatitis model, and cleared antigen+ melanoma cells in a solid tumor model. NtLNPs targeting NKG2a boosted efficacy in solid tumor models by mitigating Qa-1b mediated immunosuppression. In vivo and ex vivo, NtLNP-generated human CAR NK cells induced regression in humanized lymphoma and T cell leukemia mouse models.

Contributed by Paula Hochman

ABSTRACT: Targeted lipid nanoparticles (LNPs) offer a nonviral approach for in vivo cell engineering but efficient programming of natural killer (NK) cells remains underexplored. Here we develop NK cell-targeted LNPs (NtLNPs) using engineered biparatopic NK cell ligands to drive receptor-specific uptake and mRNA delivery. Lead NtLNPs achieve up to ~80% NK cell transfection with minimal off-target effects in mice. Systemic delivery of chimeric antigen receptor (CAR) mRNA using NtLNPs generates CAR NK cells in vivo. CD19-targeted CAR NKs completely deplete circulating B cells in healthy mice and CD3-targeted CAR NKs eliminate nearly all autoreactive T cells in an autoimmune hepatitis model, highlighting a potential advantage over CAR T therapies for T cell-driven disease. In solid tumors, NtLNPs targeting the inhibitory checkpoint NKG2A enhance antitumor efficacy by relieving Qa-1(b)-mediated immunosuppression. Lastly, we optimized NtLNPs for in vivo engineering of human CAR NK cells, enabling regression of two humanized hematologic malignancy models and establishing NtLNPs as a modular immunotherapy system.

Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute

Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (2) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (3) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. (4) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (5) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Harvard and MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. (6) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA. (7) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (9) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (10) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. (11) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (12) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (13) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (14) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. (15) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. Harvard and MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. (16) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu. Harvard and MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu. Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Boston, MA, USA. dgander@mit.edu. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA. dgander@mit.edu.

Citation: Nat Biotechnol 2026 Oct 13 Epub10/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42870042

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Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation

Featured  

(1) Saco JD (2) Karin D (3) Patten JJ (4) Bachl S (5) Ching C (6) Kale N (7) Fan Y (8) Medina E (9) Naser Al Deen N (10) Champhekar A (11) Kaelin WG (12) Schulman BA (13) Campbell KM (14) Carnevale J (15) Puig-Saus C (16) Ribas A

Cancer immunology research

Two recent back-to-back publications by Bachl et al. and Saco et al. used CRISPR-Cas9 knockout screens in primary human T cells exposed to repetitive antigen challenge and uncovered the enrichment of Cullin-RING Ligase 5 (CRL5) complex members over time with chronic antigen exposure. Knockouts of CRL5 components resulted in maintenance of antitumor effector function and delayed dysfunction. KO of these components in CAR-T or TCR-T cells improved tumor control in mice.

(1) Saco JD (2) Karin D (3) Patten JJ (4) Bachl S (5) Ching C (6) Kale N (7) Fan Y (8) Medina E (9) Naser Al Deen N (10) Champhekar A (11) Kaelin WG (12) Schulman BA (13) Campbell KM (14) Carnevale J (15) Puig-Saus C (16) Ribas A

Cancer immunology research

Two recent back-to-back publications by Bachl et al. and Saco et al. used CRISPR-Cas9 knockout screens in primary human T cells exposed to repetitive antigen challenge and uncovered the enrichment of Cullin-RING Ligase 5 (CRL5) complex members over time with chronic antigen exposure. Knockouts of CRL5 components resulted in maintenance of antitumor effector function and delayed dysfunction. KO of these components in CAR-T or TCR-T cells improved tumor control in mice.

ABSTRACT: T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8_ T cells expressing an NY-ESO-1-specific T-cell receptor and subjected them to repeated tumor cell rechallenge. These screens revealed enrichment of single-guide RNAs targeting components of Cullin-RING E3 ligases, particularly Cullin-5 (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors.

Author Info: (1) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (2) University of California, Los Angeles LA, CA United States. ROR: https:/

Author Info: (1) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (2) University of California, Los Angeles LA, CA United States. ROR: https://ror.org/046rm7j60 (3) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (4) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (5) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (6) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (7) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (8) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (9) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (10) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (11) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (12) Max Planck Institute of Biochemistry Martinsried Germany. ROR: https://ror.org/04py35477 (13) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (14) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (15) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60 (16) University of California, Los Angeles Los Angeles, CA United States. ROR: https://ror.org/046rm7j60

Citation: Cancer Immunol Res 2026 Oct 15 Epub10/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42878659

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Disruption of the CRL5 ubiquitin ligase complex enhances engineered T-cell persistence under chronic tumor antigen exposure Featured  

(1) Bachl S (2) Ching C (3) Talbot A (4) Forget A (5) Kale N (6) Kochendoerfer C (7) Nyberg WA (8) Li Z (9) Chen PA (10) Kennedy PH (11) Liu Q (12) Muldoon JJ (13) Liu C (14) Cusing G (15) Arang N (16) Krogan NJ (17) Allen GM (18) Marson A (19) Dodgson SE (20) Eyquem J (21) Carnevale J

Cancer immunology research

Two recent back-to-back publications by Bachl et al. and Saco et al. used CRISPR-Cas9 knockout screens in primary human T cells exposed to repetitive antigen challenge and uncovered the enrichment of Cullin-RING Ligase 5 (CRL5) complex members over time with chronic antigen exposure. Knockouts of CRL5 components resulted in maintenance of antitumor effector function and delayed dysfunction. KO of these components in CAR-T or TCR-T cells improved tumor control in mice.

(1) Bachl S (2) Ching C (3) Talbot A (4) Forget A (5) Kale N (6) Kochendoerfer C (7) Nyberg WA (8) Li Z (9) Chen PA (10) Kennedy PH (11) Liu Q (12) Muldoon JJ (13) Liu C (14) Cusing G (15) Arang N (16) Krogan NJ (17) Allen GM (18) Marson A (19) Dodgson SE (20) Eyquem J (21) Carnevale J

Cancer immunology research

Two recent back-to-back publications by Bachl et al. and Saco et al. used CRISPR-Cas9 knockout screens in primary human T cells exposed to repetitive antigen challenge and uncovered the enrichment of Cullin-RING Ligase 5 (CRL5) complex members over time with chronic antigen exposure. Knockouts of CRL5 components resulted in maintenance of antitumor effector function and delayed dysfunction. KO of these components in CAR-T or TCR-T cells improved tumor control in mice.

ABSTRACT: Engineered T-cell therapies are limited by progressive dysfunction under chronic tumor antigen exposure, and genetic perturbation of negative regulators has emerged as a promising strategy to sustain effector activity. We reanalyzed a genome-wide CRISPR knockout screen in primary human T cells under repetitive tumor stimulation; protein-protein interaction mapping revealed seven members of the Cullin-RING Ligase 5 (CRL5) complex as an enriched hit cluster. Knockout of any of these members (CUL5, ARIH2, RNF7, UBE2F, UBE2L3, CISH, DCUN1D3) enhanced tumor serial killing, and CUL5, the complex scaffold, emerged as the strongest target. CUL5 knockout T cells exhibited sustained cytotoxicity, elevated effector cytokine production, and fewer exhaustion marker-positive cells while retaining antigen specificity and cytokine dependence. Quantitative ubiquitylation proteomics in resting, and acutely and chronically stimulated T cells mapped CRL5-dependent candidate substrates beyond the canonical JAK/STAT axis, including nutrient transporters, receptor trafficking proteins, and TCR signaling components. The benefit of CUL5 knockout extended across CARs targeting CD19, BCMA, and HER2 with different costimulatory domains, and to 1XX-modified CAR and HLA-independent TCR architectures. Combining CUL5 ablation with a tumor-induced IL-2 circuit produced tumor control across nine rounds of repetitive stimulation, whereas either modification alone eventually failed. In vivo, CUL5 knockout BCMA CAR T cells were enriched in the bone marrow following repeated tumor rechallenge and exhibited enhanced ex vivo cytotoxicity after nearly 90 days in tumor-bearing mice. These findings position CUL5 perturbation as a strategy to improve T-cell persistence and the efficacy of adoptive cell therapies, potentially with engineered cytokine support.

Author Info: (1) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (2) Gladstone Institutes San Francisco, California United States. ROR: https://ror.

Author Info: (1) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (2) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (3) H™pital Saint-Louis Paris France. ROR: https://ror.org/049am9t04 (4) University of California San Francisco Medical Center United States. ROR: https://ror.org/01t8svj65 (5) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (6) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (7) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (8) Gladstone Institutes United States. ROR: https://ror.org/038321296 (9) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (10) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (11) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (12) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (13) UCSF San Francisco, CA United States. (14) Tango Therapeutics (United States) Boston, Massachusetts United States. ROR: https://ror.org/003x6t567 (15) University of California, San Francisco San Francisco, California United States. ROR: https://ror.org/043mz5j54 (16) University of California, San Francisco San Francisco, California United States. ROR: https://ror.org/043mz5j54 (17) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54 (18) University of California, San Francisco United States. ROR: https://ror.org/043mz5j54 (19) Gladstone Institutes San Francisco, California United States. ROR: https://ror.org/038321296 (20) UCSF San Francisco, CA United States. (21) University of California, San Francisco San Francisco, CA United States. ROR: https://ror.org/043mz5j54

Citation: Cancer Immunol Res 2026 Oct 15 Epub10/15/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42878665

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Lifestyle-induced regulatory T cell fragility primes adverse events after immune checkpoint blockade Spotlight 

(1) Patra D (2) Wolfgang K (3) Ye C (4) Rigatti L (5) Ertwine K (6) Morder KM (7) Jana J (8) Baral I (9) Hurd D (10) Bossong K (11) Mullett S (12) Dou Y (13) Gelhaus S (14) Vignali DAA (15) Davar D (16) Cillo AR (17) Delgoffe GM (18) Overacre-Delgoffe AE

Cell

Patra et al. fed mice a low-fiber, high-fat Western diet (inducing dysbiosis and outgrowth of Akkermansia) and treated them with anti-PD-1 to obtain the lifestyle-induced susceptibility to immune-related adverse events (irAEs) mouse model, LISA. LISA recapitulated the ICB toxicity profile affecting many patients, and was influenced by known demographic factors. Cytotoxic tissue-resident memory CD8+ T cells (TRM) and Tregs were increased in affected tissues. Tregs were fragile, less suppressive, and secreted IFNγ. Treg-specific disruption of IFNγ production or signaling and dietary reversal reduced irAE severity, but not antitumor efficacy. Treg fragility and cytotoxic TRM were also present in human irColitis.

Contributed by Ute Burkhardt

(1) Patra D (2) Wolfgang K (3) Ye C (4) Rigatti L (5) Ertwine K (6) Morder KM (7) Jana J (8) Baral I (9) Hurd D (10) Bossong K (11) Mullett S (12) Dou Y (13) Gelhaus S (14) Vignali DAA (15) Davar D (16) Cillo AR (17) Delgoffe GM (18) Overacre-Delgoffe AE

Cell

Patra et al. fed mice a low-fiber, high-fat Western diet (inducing dysbiosis and outgrowth of Akkermansia) and treated them with anti-PD-1 to obtain the lifestyle-induced susceptibility to immune-related adverse events (irAEs) mouse model, LISA. LISA recapitulated the ICB toxicity profile affecting many patients, and was influenced by known demographic factors. Cytotoxic tissue-resident memory CD8+ T cells (TRM) and Tregs were increased in affected tissues. Tregs were fragile, less suppressive, and secreted IFNγ. Treg-specific disruption of IFNγ production or signaling and dietary reversal reduced irAE severity, but not antitumor efficacy. Treg fragility and cytotoxic TRM were also present in human irColitis.

Contributed by Ute Burkhardt

ABSTRACT: Immune checkpoint blockade has transformed cancer therapy, but immune-related adverse events (irAEs) remain a major, sometimes fatal, limitation, and the lack of robust preclinical models has hindered mechanistic insight. We present the lifestyle-induced susceptibility to irAEs (LISA) model, in which diet-driven metabolic and microbial alterations recreate human-like susceptibility to anti-PD-1 toxicity. LISA recapitulates multi-organ irAEs with immune infiltration and cytokine production, severity depending on sex, age, treatment modality, and immunotherapy response. Mechanistically, dysbiosis marked by Akkermansia muciniphila enrichment accompanies aberrant immune activation, driving regulatory T cell (Treg) fragility and CD8+ cytotoxic effector populations, both observed in patients with irColitis. Dietary reversal, metabolite supplementation, and blocking interferon (IFN)-γ production or signaling in Tregs restored Treg stability and resolved inflammation. Human-to-mouse fecal microbiome transfer interacts with recipient diet to shape susceptibility. Together, these findings identify dietary, microbial, and immune drivers of irAEs, which can be leveraged to improve immunotherapy responses while minimizing toxicity.

Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment

Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (2) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (3) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) Division of Laboratory Animal Resources, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA. (5) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. (6) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (7) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (9) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (10) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (11) Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15213, USA. (12) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Cellular and Molecular Pathology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (13) Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA 15213, USA. (14) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (15) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (16) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Center for Systems Immunology, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15206, USA. (17) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. (18) UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15206, USA; Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15206, USA. Electronic address: overacre@pitt.edu.

Citation: Cell 2026 Oct 22 Epub10/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42913630

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A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity Spotlight 

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

(1) Léchine E (2) Cons L (3) Garnier L (4) Malinge P (5) Moine V (6) Osorio JC (7) Shang L (8) Fischer N (9) Hugues S (10) Scheiermann C (11) Ferlin W

Cancer immunology research

To overcome the dose-limiting toxicity associated with both CD47-targeting antibodies and IL-2, Léchine, Cons, and Garnier et al. developed a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) that only unmasks its components when cleavable linkers are broken by MMP9 in the TIME. In mouse models, aCD47/IL-2c was better tolerated than either component alone. Antitumor efficacy was dependent on both components, which together induced pro-inflammatory macrophage polarization and increased effector CD8+ T cell infiltration. Antitumor efficacy and tolerability were also observed for a human aCD47/IL-2c in a humanized mouse model.

Contributed by Lauren Hitchings

ABSTRACT: Cancer immunotherapies have achieved meaningful clinical benefit but remain limited by systemic toxicities that restrict the use of potent immune modulators. CD47-targeting antibodies promote tumor cell phagocytosis but are hindered by hematologic toxicity, while IL-2 activates cytotoxic lymphocytes but induces broad, dose-limiting immune activation. Here, we engineered a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) designed for tumor-selective activation. In this construct, a CD47-specific antibody (aCD47) and an IL-2/IL-2 receptor complex (IL2c) sterically and functionally suppress each other via protease-cleavable linkers, preventing CD47 blockade and IL-2 receptor engagement in circulation while enabling protease-dependent unmasking within the tumor microenvironment. A human construct demonstrated masking and protease-dependent restoration of both CD47-SIRP_ blockade and IL-2 signaling, with improved systemic tolerability in human hCD47/hSIRP_ transgenic mice, supporting translational potential. A murine analog enabled mechanistic and efficacy studies in immunocompetent tumor models. The tolerability of mouse aCD47/IL-2c was improved in comparison to individual components. Antitumor activity required both CD47 blockade and IL-2 activity, and resulted in a robust antitumor efficacy, including in an immune checkpoint-resistant melanoma model. The robust antitumor efficacy was associated with inflammatory macrophage polarization and increased numbers of effector CD8_ T cells inside the tumor. Unlike conventional CD47 antibodies or IL-2 therapies, this approach enabled coordinated, tumor-localized activation of innate and adaptive immunity while limiting systemic exposure. Together, these data highlight reciprocal masking as a clinically relevant strategy to expand the therapeutic index of immune modulators constrained by systemic toxicity.

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: http

Author Info: (1) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (2) Light Chain Bioscience (Switzerland) Plan-les-Ouates Switzerland. ROR: https://ror.org/03a17f132 (3) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (4) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (5) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (6) Memorial Sloan Kettering Cancer Center New York City, New York United States. ROR: https://ror.org/02yrq0923 (7) Light Chain Bioscience. (8) Light Chain Bioscience (Switzerland) Plan-Les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132 (9) Geneva Medical School Geneva Switzerland. (10) University of Geneva Geneva Switzerland. ROR: https://ror.org/01swzsf04 (11) Light Chain Bioscience (Switzerland) Plan-les-Ouates, Geneva Switzerland. ROR: https://ror.org/03a17f132

Citation: Cancer Immunol Res 2026 Oct 5 Epub10/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42832640

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Spatially tuned localization of interleukins and OX40 agonists enhances synergistic anti-tumor immunity Spotlight 

(1) Klich JH (2) Nejatfard A (3) Meany EL (4) Ou BS (5) Krawczyk ZD (6) Baillet J (7) Appel EA

Cell reports. Medicine

Klich et al. showed that hydrogel delivery of IL-2 and IL-12 intratumorally (IT) and CpG-adjuvanted agonistic anti-OX40 (agOX40) peritumorally (PT) increased cargo retention relative to IV delivery. Hydrogel cytokine delivery IT boosted efficacy in mouse models compared to PT or soluble IT delivery, and skewed the TIME toward antitumor Tcm cells and activated DCs. Relative to IT, PT delivery of agOX40 extended tumor control, increased Tem cells, and reduced immunosuppressive Tregs in the TdLNs and TIME. Hydrogel delivery of cytokines IT + agOX40 PT improved survival and cleared distal tumors, while IT/IT or PT/PT delivery was less active. Adding anti-PD-1 boosted long-term survival.

Contributed by Paula Hochman

(1) Klich JH (2) Nejatfard A (3) Meany EL (4) Ou BS (5) Krawczyk ZD (6) Baillet J (7) Appel EA

Cell reports. Medicine

Klich et al. showed that hydrogel delivery of IL-2 and IL-12 intratumorally (IT) and CpG-adjuvanted agonistic anti-OX40 (agOX40) peritumorally (PT) increased cargo retention relative to IV delivery. Hydrogel cytokine delivery IT boosted efficacy in mouse models compared to PT or soluble IT delivery, and skewed the TIME toward antitumor Tcm cells and activated DCs. Relative to IT, PT delivery of agOX40 extended tumor control, increased Tem cells, and reduced immunosuppressive Tregs in the TdLNs and TIME. Hydrogel delivery of cytokines IT + agOX40 PT improved survival and cleared distal tumors, while IT/IT or PT/PT delivery was less active. Adding anti-PD-1 boosted long-term survival.

Contributed by Paula Hochman

ABSTRACT: While advances in immunotherapy have revolutionized care for cancer patients, most approaches still fail to mount a robust anti-cancer effect. To address this challenge, the field has turned to combination immunotherapies, but systemic administration of potent combination therapies has resulted in severe immune-related adverse effects. Here, we use an injectable polymer-nanoparticle (PNP) hydrogel to rationally localize immunotherapeutic cytokines (IL-12 and IL-2) intratumorally and antibodies (OX40a) peritumorally. We hypothesize that selectively altering the biodistribution of these cargo enables tolerable and synergistic anti-cancer combinations. Using in vivo imaging, we demonstrate that administration sites are critical for redistributing cargo to either the tumor or tumor-draining lymph node (tdLN). Further, we demonstrate that this approach synergistically improved treatment efficacy in the B16F10 and MC38 tumor models and alters cellular phenotypes, resulting in significant tumor clearance in both single and double tumor models.

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Department of Biochemistry, Stanford University, Stanford, CA 94305, USA. (3) Department of Bioe

Author Info: (1) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (2) Department of Biochemistry, Stanford University, Stanford, CA 94305, USA. (3) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (4) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA. (5) Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA. (6) Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA. (7) Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Material Science and Engineering, Stanford University, Stanford, CA 94305, USA; Sarafan ChEM- H, Stanford University, Stanford, CA 94305, USA; Wood Institute for the Environment, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics (Endocrinology), Stanford University, Stanford, CA 94305, USA. Electronic address: eappel@stanford.edu.

Citation: Cell Rep Med 2026 Oct 9 103109 Epub10/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42854695

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XIAP inhibition augments personalized neoantigen vaccine-driven antitumor immunity in orthotopic hepatocellular carcinoma Spotlight 

(1) Zheng X (2) Fu J (3) Chen G (4) Huang Y (5) Huang J (6) Li Z (7) Zhong W (8) Wu B (9) Tang R (10) Yue Y (11) Huang T (12) Meng L (13) Mou P (14) Chen P (15) Guo L (16) Dong X (17) Liu X (18) Zeng Y (19) Cai Z

Journal for immunotherapy of cancer | Free PMC Article

Zheng et al. showed that in human HCC, XIAP is markedly upregulated and inversely correlated with CD8+ T cell tumor infiltration and RFS. Treatment of orthotopic HCC mouse models with the SMAC mimetic Birinapant boosted MHC-­I expression, reduced PD-­L1 levels, induced short-term immune cell tumor infiltration and mediated modest antitumor effects. Birinapant combined with personalized NeoVAC therapy expanded less exhausted, cytotoxic, neoantigen-­specific CD8+ Tem cells, promoted DC antigen presentation, and shifted TAMs toward a pro-­inflammatory phenotype to safely stimulate potent tumor control, immune memory, and protection against metastases.

Contributed by Paula Hochman

(1) Zheng X (2) Fu J (3) Chen G (4) Huang Y (5) Huang J (6) Li Z (7) Zhong W (8) Wu B (9) Tang R (10) Yue Y (11) Huang T (12) Meng L (13) Mou P (14) Chen P (15) Guo L (16) Dong X (17) Liu X (18) Zeng Y (19) Cai Z

Journal for immunotherapy of cancer | Free PMC Article

Zheng et al. showed that in human HCC, XIAP is markedly upregulated and inversely correlated with CD8+ T cell tumor infiltration and RFS. Treatment of orthotopic HCC mouse models with the SMAC mimetic Birinapant boosted MHC-­I expression, reduced PD-­L1 levels, induced short-term immune cell tumor infiltration and mediated modest antitumor effects. Birinapant combined with personalized NeoVAC therapy expanded less exhausted, cytotoxic, neoantigen-­specific CD8+ Tem cells, promoted DC antigen presentation, and shifted TAMs toward a pro-­inflammatory phenotype to safely stimulate potent tumor control, immune memory, and protection against metastases.

Contributed by Paula Hochman

BACKGROUND: Personalized neoantigen vaccines offer a rational immunotherapeutic strategy for hepatocellular carcinoma (HCC), but their efficacy is limited by insufficient tumor immunogenicity and an immunosuppressive tumor microenvironment. Tumor-intrinsic factors that constrain vaccine-induced immune responses in HCC are not well defined. X-linked inhibitor of apoptosis protein (XIAP) is frequently overexpressed in HCC and has been linked to immune evasion, raising the possibility that targeting XIAP may improve the effectiveness of neoantigen-based vaccination. METHODS: XIAP expression is examined in human HCC specimens using transcriptomic analysis and multiplex immunofluorescence. A personalized neoantigen vaccine (NeoVAC) is generated and evaluated in combination with Birinapant, a clinically investigated second mitochondria-derived activator of caspases (SMAC) mimetic, and IAP antagonist, in orthotopic HCC and KPC-OVA-ICC mouse models. Antitumor efficacy is assessed by bioluminescence imaging and survival analysis. Immune landscapes are characterized by flow cytometry, immunohistochemistry, multiplex immunofluorescence, and single-cell RNA sequencing. Neoantigen-specific immune responses are further assessed using functional assays. RESULTS: XIAP is markedly upregulated in human HCC and inversely associates with intratumoral CD8+T_cell infiltration and recurrence-free survival. Birinapant treatment increases major histocompatibility complex class I (MHC-I) expression, reduces PD-L1 levels, and facilitates immune-cell infiltration, but only has modest antitumor effects as monotherapy. In contrast, combining Birinapant with NeoVAC substantially improves tumor control. A notable proportion of treated mice achieves complete tumor regression, accompanied by durable protection against tumor rechallenge and metastatic dissemination. These effects are associated with the expansion of neoantigen-specific Ly6C(+)CD8(+) T cells exhibiting effector-memory features, strong cytotoxic capacity, and limited exhaustion, together with enhanced dendritic-cell antigen presentation and a shift of tumor-associated macrophages toward a pro-inflammatory M1-like phenotype. CONCLUSIONS: These data identify XIAP expression as a clinical correlate of an immune-refractory HCC phenotype and show that pharmacological IAP antagonism with Birinapant enhances tumor immunogenicity and supports antigen-specific T-cell immunity. The findings provide a preclinical rationale for combining the SMAC mimetic Birinapant with neoantigen vaccine-based immunotherapy in HCC.

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (2) T

Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (2) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China. (5) Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, China. (6) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (12) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (13) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (15) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (16) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China. (17) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com. (18) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com. Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China. (19) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China xiaoloong.liu@gmail.com lamp197311@126.com caizhixiong1985@163.com.

Citation: J Immunother Cancer 2026 Oct 9 14: Epub10/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42855228

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Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study Featured  

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

ABSTRACT: Conventional chimeric antigen receptor (CAR)-T manufacturing requires prolonged ex vivo activation and expansion, which may compromise T cell fitness and promote inflammatory differentiation. Here, we developed PrimeCAR, a 2-day manufacturing strategy combining low-intensity anti-CD3 priming with IL-7 and IL-21. Compared with conventionally manufactured CAR-T cells, PrimeCAR products exhibited a distinct transcriptional state characterized by preserved stemness-associated programs and a PrimeCAR-enriched primed naive T cell (Tn)-like state. Following antigen stimulation, PrimeCAR cells preferentially engaged proliferative programs while limiting exhaustion-associated regulators and inflammatory mediators. Functionally, PrimeCAR cells demonstrated enhanced expansion, persistence, and durable antitumor activity in xenograft models. In investigator-initiated phase I studies of relapsed or refractory B cell acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma, PrimeCAR showed encouraging clinical activity with a favorable safety profile. Together, these findings demonstrate that rapid manufacturing with controlled early T cell priming selectively restrains inflammatory programming while preserving CAR-T cell fitness, providing a practical strategy for improving CAR-T manufacturing and therapeutic performance.

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precisio

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precision-biotech.com. (2) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (3) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (4) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (5) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (6) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (7) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (8) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (9) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (10) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (11) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (12) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (13) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (14) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (15) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (16) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (17) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (18) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (19) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. Electronic address: sanbin1011@163.com. (20) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: cqian8634@gmail.com.

Citation: Cell Stem Cell 2026 Oct 13 Epub10/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42869018

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NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands Spotlight 

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Ho

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (3) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (4) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (5) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (6) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (7) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (8) Beijing Changping Laboratory, Beijing, China; School of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China. Electronic address: linxin307@tsinghua.edu.cn. (9) Beijing Changping Laboratory, Beijing, China. Electronic address: woshiwjs@hotmail.com. (10) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address: hanwdrsw@163.com.

Citation: Cell Rep Med 2026 Oct 16 103116 Epub10/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42887502

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Peripheral Blood as the Sole Source for Cancer Neoantigen and Reactive T-Cell Discovery Spotlight 

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

ABSTRACT: Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens.

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (3) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (4) Vall d'Hebron Institute of Oncology Spain. ROR: https://ror.org/054xx3904 (5) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (6) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (7) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (8) Universitat Aut˜noma de Barcelona Barcelona, Barcelona Spain. ROR: https://ror.org/052g8jq94 (9) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (10) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (11) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (12) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (13) National Institutes of Health United States. ROR: https://ror.org/01cwqze88 (14) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (15) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (16) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (17) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (18) Instituto de Investigaci—n Sanitaria Arag—n Zaragoza Spain. ROR: https://ror.org/03njn4610 (19) Stanford University Stanford, CA United States. ROR: https://ror.org/00f54p054 (20) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (21) Vall d'Hebron Institute of Oncology barcelona, barcelona, spain Spain. ROR: https://ror.org/054xx3904 (22) Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain. (23) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (24) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (25) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (26) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (27) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (28) Institut d'Investigaci— BiomŽdica de Bellvitge L'Hospitalet de Llobregat Spain. ROR: https://ror.org/0008xqs48 (29) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (30) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (31) Centre Hospitalier de l'UniversitŽ de MontrŽal Montreal Canada. ROR: https://ror.org/0410a8y51 (32) The Francis Crick Institute London United Kingdom. ROR: https://ror.org/04tnbqb63 (33) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (34) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (35) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42806482

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