Journal Articles

FAP-CD40 and PD1-IL2v combination therapy reprograms immunologically cold tumors through de novo intratumoral T cell-dendritic cell clusters Spotlight 

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

(1) Nguyen TT (2) Gómez H (3) Lutge M (4) Yángüez E (5) Hüsser T (6) Nassiri S (7) Trumpfheller C (8) Colombetti S (9) Codarri Deak L (10) Umaña P (11) Tugues S (12) Grazina de Matos I (13) Kunz L

Journal for immunotherapy of cancer | Free PMC Article

In a KPC tumor model, Nguyen et al. combined a FAP-targeted CD40 agonist (FAP-CD40; localizes CD40 stimulation to the TME) and PD1–IL-2v (targets a mutated IL-2 to PD-1+ T cells and not Tregs). FAP-CD40 alone activated TME cDC1s, which migrated to tdLNs. Combination therapy expanded TME T cells and increased CD4+/CD8+/cDC1 clustering and therapeutic efficacy (dependent on both CD4+ and CD8+ T cells) compared to monotherapies. FTY720 blockade of LN egress did not preclude clustering or efficacy, suggesting activation of TME T cells. Combination therapy boosted TME T cell Th1 gene expression, TNFα/IFNγ production, and Nur77 promoter activity.

Contributed by Alex Najibi

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a major challenge for immunotherapy due to its immunologically cold tumor nature, characterized by poor T cell infiltration and a highly suppressive tumor microenvironment. Here, we propose a novel strategy, combining fibroblast activation protein (FAP)-CD40 to activate dendritic cells (DCs) in the tumor microenvironment and programmed cell death protein-1 (PD1)-interleukin 2v (IL2v) to promote the expansion and differentiation of tumor-infiltrating T cells. We hypothesize that this combination will synergistically enhance both T cell priming and expansion directly within pancreatic 4662 KPC tumors, which recapitulate the immunologically cold features of human PDAC. METHODS: Immune cell distribution and abundance following FAP-CD40/PD1-IL2v monotherapy or combination therapy were analyzed using multiplexed confocal imaging (3D immune phenotyping). FTY720 studies assessed the contribution of lymph node priming in treatment efficacy, while CD4+/CD8+ T cell depletion experiments identified the roles of these subsets in combination therapy. T cell functionality was further assessed through ex vivo restimulation assays and single-cell RNA sequencing. RESULTS: Combination therapy induced dense intratumoral clusters of CD4(+) and CD8(+) T cells, colocalized with type 1 conventional DCs, termed as T cell-DC clusters (TDCs). These TDCs were strongly associated with tumor regression, which required both CD4(+) and CD8(+) T cells. Furthermore, T cells from combination-treated tumors showed enhanced functionality, with increased tumor necrosis factor-alpha and interferon-gamma production compared with monotherapy groups. Single-cell RNA sequencing revealed polarization of CD4(+) T cells toward a T helper cell 1 phenotype in combination-treated tumors. CONCLUSION: The combination of FAP-CD40 and PD1-IL2v offers a promising strategy for treating poorly infiltrated, cold tumors. By driving T cell infiltration, promoting de novo TDC formation and orchestrating local antitumor immunity, this strategy provides a foundation for future therapies targeting immunotherapy-resistant tumors.

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Ba

Author Info: (1) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (2) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (3) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (4) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (5) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (6) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (7) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (8) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland. (9) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (10) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (11) Institute of Experimental Immunology, UniversitŠt ZŸrich, ZŸrich, Switzerland. Department of Immunology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany. (12) Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. (13) Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland leo.kunz@roche.com.

Citation: J Immunother Cancer 2026 May 28 14: Epub05/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42208978

Tags:

Pembrolizumab plus high-dose IL-2 in advanced clear cell renal cell carcinoma: six-year survival outcomes and molecular signatures from a phase 2 trial Spotlight 

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

(1) Johnson JS (2) Miller JW (3) Hatoum F (4) Schell MJ (5) Yu X (6) Roman Souza G (7) Mizelle S (8) Gullapalli K (9) Fazili A (10) Jain R (11) Chatzkel J (12) Cen L (13) Dhillon J (14) Cubitt C (15) Yao J (16) Whiting J (17) Li J (18) Swank J (19) Jameel G (20) Zhang J (21) Wang X (22) Spiess PE (23) Fishman M (24) Chahoud J

Nature communications

In a phase 2 clinical trial of a short-course regimen (median 7 months) of pembrolizumab (anti-PD-1) plus high-dose IL-2 in patients with advanced ccRCC, Johnson et al. reported that at a median follow-up of over 6 years, the ORR was 73%, with 42% CRs and a 92% DCR. Median OS was over 84 months, and median PFS was 19.3 months. Patients were able to remain off treatment for a median of 23.8 months, with 42% of patients off treatment at 5 years. Potential biomarkers for durable clinical benefit included elevated CD16+ NK cells, enhanced innate immunity, reduced PD-1+ T cells, and patterns of IL-2-induced immune remodeling.

Contributed by Lauren Hitchings

ABSTRACT: Prolonged or indefinite systemic therapy remains standard for advanced clear cell renal cell carcinoma (ccRCC), often resulting in cumulative toxicities and treatment burden. We conducted a single-arm phase 2 trial (ClinicalTrials.gov identifier: NCT02964078) of a fixed-duration regimen of anti-PD1 pembrolizumab plus high-dose interleukin-2 in treatment-naive advanced ccRCC. Primary objectives of safety and response were previously reported. The study met its primary endpoint with an overall response rate exceeding the pre-specified threshold of 45%. Here we report long-term follow-up (median follow-up of 76.4 months) including overall response, progression-free survival, treatment-free interval, and correlative analysis. Among 26 patients treated, the objective response rate was 73%, with complete responses in 42% of patients. Median overall survival was >84 months with a 5-year restricted mean survival time of 48.6 months. Median progression-free survival was 19.3 months, and median treatment-free interval was 23.8 months. 42% of patients remained treatment-free at the 5-year timepoint. No grade 5 adverse events occurred, and no patients with durable disease control experienced persistent grade ≥2 toxicities. Correlative analyses identified exploratory immune patterns associated with durable benefit, including enrichment of CD16⁺ natural killer cells, suppression of PD-1⁺ T-cell frequencies, and coordinated chemokine, complement, and PKC/TGF-β pathway activation.

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary

Author Info: (1) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (2) USF Health Morsani College of Medicine, Tampa, FL, USA. (3) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (4) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (5) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (6) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (7) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (8) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (9) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (10) Department of Genitourinary Oncology, Weill Cornell Medicine, New York, NY, USA. (11) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (12) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (13) Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (14) Immune Monitoring Core, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (15) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (16) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (17) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (18) Department of Pharmacy, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (19) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (20) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (21) Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (22) Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA. (23) USF Health Morsani College of Medicine, Tampa, FL, USA. Tampa General Hospital Cancer Institute, Tampa, FL, USA. (24) Department of Genitourinary Oncology, Orlando Health Cancer Institute, Orlando, FL, USA. Jad.Chahoud@orlandohealth.com.

Citation: Nat Commun 2026 May 25 Epub05/25/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42185255

Tags:

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

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

Cancer immunology research

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

Contributed by Katherine Turner

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

Cancer immunology research

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

Contributed by Katherine Turner

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

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

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

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

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

Tags:

Immune-remodeling mRNAs expressing IRF8 or NIK generate durable antitumor immunity in multiple cancer models Spotlight 

(1) Gupta A (2) Das R (3) Reed K (4) Jeon T (5) Nguyen QTC (6) Rudra A (7) Ge X (8) Trongjit S (9) Vanrobaeys YS (10) Langer R (11) Weissleder R (12) Garris C (13) Anderson DG

Nature biotechnology

In mice, i.t. or i.v. delivery of CKK-E12-LNPs loaded with immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase (NIK) or IFN regulatory factor 8 (IRF8) induced (1) APC activation and maturation into cDC1s, (2) a release of immunostimulatory cytokines, (3) accumulation of NKT and γδT cells in tumors, and (4) priming of antitumor CD8+ T cells, which infiltrated and eliminated tumors and protected mice from rechallenge. In combination with mRNA encoding OVA, IR-mRNA prevented growth of OVA+ tumors. IR-mRNAs also synergized with anti-PD-1, and enhanced humoral and adaptive immune responses to infectious disease antigens.

Contributed by Lauren Hitchings

(1) Gupta A (2) Das R (3) Reed K (4) Jeon T (5) Nguyen QTC (6) Rudra A (7) Ge X (8) Trongjit S (9) Vanrobaeys YS (10) Langer R (11) Weissleder R (12) Garris C (13) Anderson DG

Nature biotechnology

In mice, i.t. or i.v. delivery of CKK-E12-LNPs loaded with immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase (NIK) or IFN regulatory factor 8 (IRF8) induced (1) APC activation and maturation into cDC1s, (2) a release of immunostimulatory cytokines, (3) accumulation of NKT and γδT cells in tumors, and (4) priming of antitumor CD8+ T cells, which infiltrated and eliminated tumors and protected mice from rechallenge. In combination with mRNA encoding OVA, IR-mRNA prevented growth of OVA+ tumors. IR-mRNAs also synergized with anti-PD-1, and enhanced humoral and adaptive immune responses to infectious disease antigens.

Contributed by Lauren Hitchings

ABSTRACT: Although immunotherapy has benefited a subset of persons with cancer, its broader efficacy remains limited, primarily because of an immunosuppressive tumor microenvironment characterized by insufficient numbers of functional tumor-specific T cells, antigen-presenting cells (APCs) and tumor-infiltrating lymphocytes. Here we engineer immune cells in the tumor microenvironment using lipid nanoparticles (LNPs) to deliver immune-remodeling mRNAs (IR-mRNAs) encoding NF-κB-inducing kinase or interferon regulatory factor 8. These IR-mRNAs activate APCs in tumors, significantly increasing activated type 1 conventional dendritic cells, immunostimulatory cytokines and priming antitumor CD8+ T cells. IR-mRNAs encapsulated in LNPs elicited durable antitumor responses in multiple syngeneic mouse tumor models through both intratumoral and intravenous delivery. Coadministration of IR-mRNA and ovalbumin mRNA elicited a ~10-fold increase in antigen-specific CD8+ T cell responses, sustained long-term memory and effectively prevented tumor growth in vaccinated mice. Additionally, coadministration of IR-mRNA and hemagglutinin mRNA enhanced the humoral response ~5-fold and the cellular response ~15-fold, underscoring their potential as adjuvants for boosting adaptive immunity.

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) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. (3) 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. (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. Department of Chemical Engineering, 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) Center for Systems Biology, Massachusetts General Hospital, Boston, 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) Bioinformatics & Computing Core Facility of the Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, 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 Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. (11) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Department of Radiology, Massachusetts General Brigham, Boston, MA, USA. (12) Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. cgarris@mgh.harvard.edu. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. cgarris@mgh.harvard.edu. (13) 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.

Citation: Nat Biotechnol 2026 May 13 Epub05/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42129506

Tags:

Polymer-mRNA complexes for monocyte-trafficked, lymph node-targeted cancer vaccination Spotlight 

Qiongzhe Ren # 1, Xiaofei Zhao # 1, Lili Zhou # 2, Ruonan Ye 1, Liguo Chen 1, Keyun Ren 3, Xijun Piao 3, Yihan Zhou 4, Yiming Qi 5, Kevin C Chan 4, Li Cao 6, Liang Du 7, Peng Gao 7, Bo Ying 7, Chao Deng 1, Fenghua Meng 1, Fangfang Zhou 8, Congcong Xu 9 10 11, Zhiyuan Zhong 12 13 14

Nature biomedical engineering

To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.

Contributed by Lauren Hitchings

Qiongzhe Ren # 1, Xiaofei Zhao # 1, Lili Zhou # 2, Ruonan Ye 1, Liguo Chen 1, Keyun Ren 3, Xijun Piao 3, Yihan Zhou 4, Yiming Qi 5, Kevin C Chan 4, Li Cao 6, Liang Du 7, Peng Gao 7, Bo Ying 7, Chao Deng 1, Fenghua Meng 1, Fangfang Zhou 8, Congcong Xu 9 10 11, Zhiyuan Zhong 12 13 14

Nature biomedical engineering

To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.

Contributed by Lauren Hitchings

ABSTRACT: Lymph nodes are the primary sites where adaptive immunity is initiated, yet most messenger RNA cancer vaccines reach them inefficiently and instead accumulate in organs such as the liver, limiting therapeutic potency and increasing systemic toxicity. Here we developed a transferrin receptor-associating polyplex formed by electrostatic complexation of mRNA with low-molecular-weight polyethylenimine that had been chemically modified with cyclic disulfide monomers to enhance nucleic acid binding stability, enable thiol-based transferrin receptor engagement and reduce off-target liver uptake. After subcutaneous administration, these polyplexes activated innate immunity, rapidly recruited monocytes with high transferrin receptor expression and bound these cells through cyclic disulfide-mediated interactions. Monocytes then trafficked the vaccine to draining lymph nodes, where mRNA translation and antigen presentation occurred. Delivery of ovalbumin and interleukin 12 mRNA elicited strong antigen-specific cytotoxic T cell responses and inhibited melanoma progression and metastatic disease. Studies using Survivin and human papillomavirus antigens in distinct tumour models demonstrated broad applicability. This monocyte-driven lymph node-targeting strategy enables potent and selective delivery of mRNA cancer vaccines.

Author Info: 1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. 2Institutes of Biology and Medical Scien

Author Info: 1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. 2Institutes of Biology and Medical Science, Soochow University, Suzhou, P. R. China. 3Catug Biotechnology Co. Ltd, Suzhou, P. R. China. 4Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, P. R. China. 5School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China. 6College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. 7Suzhou Abogen Biosciences Co. Ltd, Suzhou, P. R. China. 8Institutes of Biology and Medical Science, Soochow University, Suzhou, P. R. China. zhoufangfang@suda.edu.cn. 9Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 10College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 11International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn. 12Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. 13College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. 14International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn. #Contributed equally.

Citation: Nat Biomed Eng 2026 May 5 Epub05/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42086923

Tags:

    Ferroptosis-armed dendritic cell vaccines for glioma immunotherapy Spotlight 

    Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2

    Nature communications

    A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.

    Contributed by Alex Najibi

    Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2

    Nature communications

    A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.

    Contributed by Alex Najibi

    ABSTRACT: The type of cell death has proven to play a crucial role in cancer immunotherapy efficacy. Immunogenic cell death (ICD) enhances tumor adjuvanticity and antigenicity by releasing danger signals and altering the immune peptidome. The immunogenicity of ferroptosis, an iron-dependent form of cell death, remains uncertain. Here, we show that dendritic cell (DC) vaccines loaded with ferroptotic lysates protect mice against glioma growth, inducing IFN-_ production, and promoting robust CD8_ T cell infiltration, activation, and effector memory formation in the tumor microenvironment. The intrinsic immunogenicity of ferroptosis was independent of the glioma type and the ferroptosis inducer. Instead, it critically required the presence of the damage-associated molecular patterns calreticulin and ATP, rather than involving HMGB1-TLR4 signaling. However, supplementing these DAMPs into DC vaccines loaded with non-ICD lysates did not restore efficacy to the level of the ferroptosis-based DC vaccine, suggesting a more complex mechanism beyond a purely DAMP-mediated effect. These findings demonstrate that ferroptosis-loaded DC vaccines elicit a potent, tumor-specific immune response, capable of eradicating intracranial gliomas in mice, which highlights their potential in cancer immunotherapy.

    Author Info: 1Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent Unive

    Author Info: 1Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 2Cancer Research Institute Ghent, Ghent, Belgium. 3Institute of Neurosciences, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia. 4Thoracic Tumor Immunology Laboratory (TTIL), Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Science, Ghent University, Ghent, Belgium. 5VIB Proteomics Core, VIB, Ghent, Belgium. 6VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium. 7Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 8myNEO Therapeutics, Ghent, Belgium. 9IBiTech-MEDISIP-Infinity Laboratory, Department of Electronics and Information Systems, Faculty of Engineering and Architecture, Ghent University, Ghent, Belgium. 10Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 11Neurology Clinic, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany. 12Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France. 13Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 144Brain, Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. 15Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia. 16VIB Center for Inflammation Research, Ghent, Belgium. 17Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium. 18Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. elena.catanzaro@ugent.be. 19Cancer Research Institute Ghent, Ghent, Belgium. elena.catanzaro@ugent.be. #Contributed equally.

    Citation: Nat Commun 2026 May 7 Epub05/07/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42098128

    Tags:

      Intermetallic nanoassemblies potentiate systemic STING activation Spotlight 

      Xingwu Zhou # 1 2, Xiang Ling # 1 2, Xiaoqi Sun 1 2, Ziye Wan 1 2, Tobias Dwyer 3, Timothy C Moore 3, Quguang Li 1 2, Hannah E Dobson 1 2, Qi Wu 1 2, Xiangbo Kong 4, Fang Xie 1 2, Xinran An 1 2, Jingyao Gan 1 2, Kaikai Wang 1 2, Young Seok Cho 1 2, Wang Gong 5, Katherine Dong 1 2, Jie Zhang 1 2, Mariko Takahashi 1 2, Cheng Xu 1 2, Swetha Kodamasimham 1 2, Jie Xu 4, Vilma Yuzbasiyan-Gurkan 6 7, Steven B Chinn 8, Anna Schwendeman 1 2, Sharon C Glotzer 2 3, Yu Leo Lei 5, James J Moon 1 2 3 9 10

      Science

      Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.

      Contributed by Shishir Pant

      Xingwu Zhou # 1 2, Xiang Ling # 1 2, Xiaoqi Sun 1 2, Ziye Wan 1 2, Tobias Dwyer 3, Timothy C Moore 3, Quguang Li 1 2, Hannah E Dobson 1 2, Qi Wu 1 2, Xiangbo Kong 4, Fang Xie 1 2, Xinran An 1 2, Jingyao Gan 1 2, Kaikai Wang 1 2, Young Seok Cho 1 2, Wang Gong 5, Katherine Dong 1 2, Jie Zhang 1 2, Mariko Takahashi 1 2, Cheng Xu 1 2, Swetha Kodamasimham 1 2, Jie Xu 4, Vilma Yuzbasiyan-Gurkan 6 7, Steven B Chinn 8, Anna Schwendeman 1 2, Sharon C Glotzer 2 3, Yu Leo Lei 5, James J Moon 1 2 3 9 10

      Science

      Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.

      Contributed by Shishir Pant

      ABSTRACT: Natural systems use metal ions to form ordered structures that regulate biological processes, inspiring the rational design of nanotherapeutics. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway drives antitumor immunity but has been difficult to activate systemically owing to poor pharmacology and toxicity. Here, we report CRYSTAL, a structurally ordered intermetallic nanoparticle for potent systemic STING activation. CRYSTAL self-assembles from manganese ions intercalated with cyclic dinucleotides, enabling precise structural control. At an ultralow intravenous dose (0.003 milligrams per kilogram), CRYSTAL activated STING in mice, dogs, and nonhuman primates without cytokine release syndrome. CRYSTAL induced robust tumor regression in advanced murine and rabbit models, remodeled immunosuppressive environments, and promoted host STING-dependent CD8(+) T cell priming. CRYSTAL activated interferon responses in human head and neck squamous cell carcinoma biopsies, underscoring its translational potential for cancer immunotherapy.

      Author Info: 1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. 2Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. 3Department of Chemical En

      Author Info: 1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. 2Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. 3Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA. 4Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA. 5Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 6Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA. 7Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA. 8Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA. 9Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. 10Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. #Contributed equally.

      Citation: Science 2026 May 7 392:eadx1893 Epub05/07/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42096576

      Tags:

        Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1 Featured  

        (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

        Nature

        Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

        (1) Tselikas L (2) Susini S (3) Texier M (4) Yurchenko A (5) Routier E (6) Amini-Adle M (7) Tihic E (8) Mouraud S (9) Danlos FX (10) Ammari S (11) Raoult T (12) Roy S (13) Bredel D (14) Farhane S (15) Cassard L (16) Molinaro I (17) Eggermont A (18) Soria JC (19) Zitvogel L (20) Massard C (21) Paci A (22) de Baere T (23) Scoazec JY (24) Chaput N (25) Nikolaev S (26) Meyer N (27) LebbŽ C (28) Dalle S (29) Robert C (30) Marabelle A

        Nature

        Tselikas and Susini et al. reported the results of the phase 1b NIVIPIT trial, in which 61 patients with untreated metastatic melanoma were treated with intravenous (i.v.) nivolumab (anti-PD-1) in combination with either i.v. or intratumoral (i.t.) ipilimumab (anti-CTLA-4). Patients who received i.t. anti-CTLA-4 had antitumor responses in both injected and uninjected lesions, and had fewer grade 3 or 4 treatment-related adverse events. The presence of Tregs and M2-like macrophages at baseline, high FcγR expression, and a decrease in activated Tregs on treatment were associated with durable clinical benefit, regardless of the anti-CTLA-4 administration route.

        ABSTRACT: Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer(1). Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1_mg_kg(-1)) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3_mg_kg(-1)) or intravenous ipilimumab (3_mg_kg(-1)). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (T(reg)) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural T(reg) cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fc_ receptor (Fc_R) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated T(reg) cell and Fc_R(+) M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

        Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie I

        Author Info: (1) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (2) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (3) Gustave Roussy, Service de Biostatistiques et d'EpidŽmiologie (SBE), UniversitŽ Paris Saclay, Villejuif, France. INSERM U1018, ONCOSTAT, Equipe LabellisŽe Ligue contre le Cancer, Villejuif, France. (4) INSERM U981, Gustave Roussy, Villejuif, France. (5) Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (6) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. (7) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (8) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (9) INSERM CIC 1428, BIOTHERIS, Villejuif, France. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (10) Gustave Roussy, DŽpartement d'Imagerie MŽdicale, Villejuif, France. (11) Gustave Roussy, Service de Promotion d'Etudes Cliniques, DRC, Villejuif, France. (12) INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (13) INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. (14) INSERM CIC 1428, BIOTHERIS, Villejuif, France. (15) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (16) Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (17) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (18) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (19) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U1015, Immunologie des tumeurs et immunothŽrapie contre le cancer, Villejuif, France. (20) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. (21) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, Service de Pharmacologie, DŽpartement de Biologie et Pathologie mŽdicales, Villejuif, France. (22) INSERM CIC 1428, BIOTHERIS, Villejuif, France. Gustave Roussy, Radiologie Interventionnelle, DŽpartement d'AnesthŽsie Chirurgie et Interventionnel (DACI), Villejuif, France. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. (23) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. Gustave Roussy, DŽpartement de Biologie et Pathologie MŽdicale, Villejuif, France. (24) UniversitŽ Paris-Saclay, Gustave Roussy, INSERM, Laboratoire d'Immunomonitoring en Oncologie US23, BiothŽrapies Innovantes U1363, Villejuif, F-94805, France. (25) INSERM U981, Gustave Roussy, Villejuif, France. (26) CHU de Toulouse, Service d'Oncodermatologie, IUCT-O, Toulouse, France. INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France. UniversitŽ Toulouse III - Paul Sabatier, DŽpartement de Dermatologie, Toulouse, France. (27) UniversitŽ Paris CitŽ, AP-HP Dermato-oncologie et CIC, Institut du Cancer APHP nord, Paris, France. INSERM U1342-Equipe 1-CNRS EMR8000, H™pital Saint Louis, Paris, France. (28) Hospices Civils de Lyon, DŽpartement de Dermatologie, Lyon, France. INSERM U1052-CNRS UMR5286, PlasticitŽ Tumorale dans le MŽlanome, Centre de Recherche en CancŽrologie de Lyon, Centre LŽon BŽrard, Lyon, France. UniversitŽ Claude Bernard Lyon 1, Lyon, France. (29) UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. INSERM U981, Gustave Roussy, Villejuif, France. Gustave Roussy, Dermatologie, DŽpartement de MŽdecine Oncologique, Villejuif, France. (30) INSERM CIC 1428, BIOTHERIS, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. INSERM U1015, Laboratoire de Recherche Translationnelle en ImmunothŽrapie (LRTI), Villejuif, France. aurelien.marabelle@gustaveroussy.fr. UniversitŽ Paris Saclay, Faculty of Medicine, Villejuif, France. aurelien.marabelle@gustaveroussy.fr. Gustave Roussy, DŽpartement d'Innovation ThŽrapeutique et des Essais PrŽcoces, Villejuif, France. aurelien.marabelle@gustaveroussy.fr.

        Citation: Nature 2026 Apr 29 Epub04/29/2026

        Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056527

        Tags:

        The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion Spotlight 

        (1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

        Developmental cell

        Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

        Contributed by Shishir Pant

        (1) Wang L (2) Harris CR (3) Dudgeon C (4) Prela O (5) Cazares de Menezes J (6) Shih CH (7) Davidson C (8) Casabianca A (9) De S (10) Narrow W (11) Becker J (12) Grandgenett PM (13) Hollingsworth MA (14) Grem JL (15) Kim M (16) Hong Y (17) Gerber S (18) Vertino PM (19) Gao C (20) Klamer Z (21) Repesh A (22) Hao Y (23) Ryan AT (24) Breitenbach M (25) Bianchi A (26) Datta J (27) Altman BJ (28) Haab B (29) Carpizo DR

        Developmental cell

        Wang, Harris, and Dudgeon et al. identified the circadian rhythm gene Dec2 as a tumor-intrinsic regulator of dormancy and immune evasion in pancreatic cancer models. Dormant PDAC cells and occult disseminated tumor cells expressed high levels of Dec2, which repressed multiple components of the MHC-I antigen presentation pathway and reduced T cell-mediated cytotoxicity. Tumor surface MHC-I levels oscillated in antiphase to Dec2. Dec2 deletion restored antigen presentation, repolarized the PDAC TME from immune-cold to inflamed, and improved survival in immunocompetent (Ink4a.1 and 6419c5 models), but not immunodeficient mice.

        Contributed by Shishir Pant

        ABSTRACT: The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

        Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical O

        Author Info: (1) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (2) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (3) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (5) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (6) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (7) Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (8) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (9) Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. (11) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (12) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (13) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (14) Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. (15) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (16) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (17) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (18) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (19) Center for Advanced Research Technologies, University of Rochester Medical Center, Rochester, NY, USA. (20) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (21) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (22) Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (23) Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (24) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (25) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (26) Dewitt Daughtry Department of Surgery, Division of Surgical Oncology, University of Miami Miller School of Medicine, Miami, FL, USA. (27) Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. (28) Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA. (29) Department of Surgery, Division of Surgical Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA. Electronic address: darren_carpizo@urmc.rochester.edu.

        Citation: Dev Cell 2026 Apr 28 Epub04/28/2026

        Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42055006

        Tags:

        Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma Spotlight 

        (1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

        Journal for immunotherapy of cancer | Free PMC Article

        Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

        Contributed by Alex Najibi

        (1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

        Journal for immunotherapy of cancer | Free PMC Article

        Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

        Contributed by Alex Najibi

        BACKGROUND: Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown. METHODS: We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay. RESULTS: Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T_cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T_cells (p=0.06). CONCLUSIONS: Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.

        Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney

        Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (3) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (4) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (5) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (6) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (7) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (8) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (9) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (10) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (11) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (12) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (13) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (14) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (15) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (16) F Hoffmann-La Roche Ltd, Basel, Switzerland. (17) F Hoffmann-La Roche Ltd, Basel, Switzerland. Genentech Inc, South San Francisco, California, USA. (18) Genentech Inc, South San Francisco, California, USA. (19) Genentech Inc, South San Francisco, California, USA. (20) Genentech Inc, South San Francisco, California, USA. (21) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Ludwig Institute for Cancer Research, Baltimore, Maryland, USA. (22) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (23) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (24) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (25) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (26) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (27) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (28) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu. (29) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu.

        Citation: J Immunother Cancer 2026 Apr 21 14: Epub04/21/2026

        Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42014205

        Tags:
        Close Modal

        Subscribe to our mailing list

        GDPR Marketing Permissions

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

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

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

        Close Modal

        Small change for you. Big change for us!

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

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

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

        All transactions are securely made through Stripe.