Journal Articles

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression

(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

Nature biotechnology

To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

Contributed by Ute Burkhardt

(1) Marks A (2) Siu S (3) Bianchini F (4) Wang C (5) Lakshmi A (6) Phelan M (7) Zhu A (8) Moon C (9) Morla-Folch J (10) Teunissen AJP (11) Amabile A (12) Baccarini A (13) Merad M (14) Brody JD (15) Dong Y (16) Brown BD

Nature biotechnology

To study how cell type-specific expression on mRNA-encoded proteins influences immunity, Marks and Siu et al. incorporated synthetic microRNA target sites into the mRNA. LNP-delivered mRNA did not need to be directly expressed in professional APCs (pAPCs), and expression in muscle cells was sufficient or stronger in immune response induction than pAPCs. mRNA expression in hepatocytes dampened the CD8+ T cell response and reduced mRNA vaccine control of tumor growth. Silencing mRNA expression in hepatocytes reversed these effects and, when mRNA vaccines were used to expand transferred T cells, reduced liver T cell infiltration and toxicity.

Contributed by Ute Burkhardt

ABSTRACT: Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Author Info: (1) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (2) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (3) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (4) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (5) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (6) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (7) Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (8) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (12) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (16) Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. brian.brown@mssm.edu.

Citation: Nat Biotechnol 2026 Apr 29 Epub04/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42056385

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Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer

(1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

Cancer cell

Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

Contributed by Shishir Pant

(1) Kureshi CTS (2) Walsh MJ (3) Kureshi R (4) Cardot-Ruffino V (5) Agardy DA (6) Ali LR (7) Dougan JM (8) Qiang L (9) Shen J (10) Zuo C (11) Lenehan PJ (12) Wang SJ (13) Chang E (14) Remland J (15) Brais L (16) Clancy TE (17) Cleary JM (18) Hornick JL (19) Huffman BM (20) Mancias JD (21) Molina G (22) Fairweather M (23) Nowak JA (24) Perez KJ (25) Rubinson DA (26) Slater S (27) van Dams R (28) Wang J (29) Wolpin BM (30) Zhao L (31) Barrientos K (32) Novosiadly R (33) Broz M (34) Singh H (35) Dougan M (36) Dougan SK

Cancer cell

Kureshi et al. showed that localized STING agonist combined with anti-CTLA-4 and anti-PD-1 induced durable tumor remission and memory in poorly immunogenic subcutaneous and orthotopic PDAC models, including β2m-/- tumors. Triple therapy increased activated cDC2-to-cDC1 ratios and cDC2 accumulation. Tumor control required tumor antigen-loaded cDC2 priming of IFNγ-producing Th1 CD4+ T cells in tumor-draining lymph nodes, but was independent of cDC1s, CD8+ T cells, and tumor cell MHC-I. In multiagent chemotherapy-treated PDAC patients, CD4+ T cells and cDC2s persisted, even after treatment.

Contributed by Shishir Pant

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8(+) T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8(+) T cells or tumor cell MHC expression but instead requires IFN_-producing CD4(+) T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4(+) T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4(+) T cell-IFN_ axis could be efficacious in PDAC.

Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farbe

Author Info: (1) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (2) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School Program in Virology, Boston, MA, USA. (3) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (4) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (5) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (6) Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (7) Brookline High School, Brookline, MA, USA. (8) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (9) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (10) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. (11) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (12) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (13) Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (14) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (15) Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (16) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (17) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (18) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (19) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (20) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (21) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (22) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (23) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Oncologic Pathology, Boston, MA, USA. (24) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (25) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (26) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (27) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Radiation Oncology, Boston, MA, USA. (28) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Division of Surgical Oncology, Boston, MA, USA. (29) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (30) Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Department of Pathology, Boston, MA, USA. (31) Bristol Myers Squibb, Princeton, NJ, USA. (32) Bristol Myers Squibb, Princeton, NJ, USA. (33) Bristol Myers Squibb, Princeton, NJ, USA. (34) Harvard Medical School, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA. (35) Harvard Medical School Program in Immunology, Boston, MA, USA; Massachusetts General Hospital, Department of Medicine, Division of Gastroenterology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. (36) Harvard Medical School Program in Immunology, Boston, MA, USA; Dana-Farber Cancer Institute, Department of Cancer Immunology & Virology, Boston, MA, USA. Electronic address: stephanie_dougan@dfci.harvard.edu.

Citation: Cancer Cell 2026 May 7 Epub05/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102812

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Cancer stem cells orchestrate immune evasion through extracellular vesicle-mediated non-canonical signaling pathways

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

(1) Fan G (2) Jin J (3) Wang J (4) Xu J (5) Ge W (6) Liu S (7) Tang L (8) Reziya W (9) Yang X (10) Li J (11) Ng LG (12) Di L (13) Zheng Y (14) Lan F (15) Chen S (16) Zhang Y (17) Wang X (18) Gao D (19) Liu X (20) Sun H (21) Liu Y (22) Li T (23) Cao Y (24) Tao Z (25) Liu W (26) Wang H

Cancer cell

Fan et al. found that in patient specimens of untreated TNBC, cancer stem cells produced extracellular vesicles enriched for TSPAN8 (EVs-TSPAN8), which interacted with CD103 on T cells via a paracrine signaling mechanism – independent of canonical EV internalization – inducing activation of the LKB1-AMPK-FOXP3 axis. This resulted in enhanced Foxp3 expression, which further increased CD103 expression, resulting in a positive feedback loop that enhanced the formation of pro-tumor CD103+Foxp3+ Tregs. In mouse models of TNBC, neutralizing EVs-TSPAN8+ synergized with anti-PD-1, reducing tumor growth and increasing survival.

Contributed by Lauren Hitchings

ABSTRACT: Tumor cells evade anti-tumor immunity by reprogramming tumor microenvironment (TME). Using multiplexed single-cell proteomics to analyze 50 TME-associated proteins across treatment-naive triple-negative breast cancer (TNBC) specimens, we discovered that cancer stem cells (CSCs) drive differentiation and expansion of regulatory T cells (Tregs) via extracellular vesicle (EV)-mediated paracrine signaling. TSPAN8, an integral membrane protein on CSC-derived EVs, interacts with CD103 (integrin αEβ7) on T cells, triggering the formation of LKB1-STRAD-MO25 complex and sequential phosphorylation of LKB1 and AMPKα. This cascade enhances FOXP3 expression, which transactivates CD103, creating a positive feedback loop that drives clonal expansion of immunosuppressive CD103+FOXP3+ Tregs and their associated niche. This EV membrane topology-based mechanism operates independently of canonical EV cargo internalization. Neutralizing EVs-TSPAN8+ with a monoclonal antibody synergized with anti-PD-1 therapy in preclinical models, suggesting a potential approach targeting both CSCs and TME immunosuppression, particularly in TNBC subpopulation with high TSPAN8+ CSCs.

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Cent

Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China; Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 20080, China; Breast and Thyroid Surgery Department, General Surgery Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (2) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (3) Department of Breast, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, No. 910 Hengshan Road, Shanghai, China. (4) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (5) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (6) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (7) Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiao Tong University School of Medicine, Suzhou 21500, China. (8) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (9) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (10) State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. (11) Research Unit of Immune Regulation and Immune Diseases of Chinese Academy of Medical Sciences, Shanghai Jiao Tong University School of Medicine-Affiliated Renji Hospital, Shanghai 200127, China. (12) Cancer Center, Faculty of Health Science, University of Macau, Macau 999078, China. (13) State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Shanghai Cancer Center, Fudan University, Shanghai 200032, China. (14) Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. (15) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (16) Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (17) Department of Surgery, The Chinese University of Hong Kong Prince of Wales Hospital, Shatin 999077, Hong Kong SAR, China. (18) State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, CAS, Shanghai 200031, China. (19) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China. (20) Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. (21) Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai 201800, China. (22) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. (23) Department of Neurosurgery, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: gem23@163.com. (24) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: drtaozhh@126.com. (25) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: liuwenting1015@163.com. (26) Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; State Key Laboratory of Systems Medicine for Cancer, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20080, China. Electronic address: whx365@126.com.

Citation: Cancer Cell 2026 May 7 Epub05/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42102811

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Foxp3 drives context-dependent epigenetic programs that define regulatory T cell molecular identity and function

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

(1) Wei Y (2) Ago H (3) Murakami R (4) Funatsu S (5) Osaki M (6) Nakajima A (7) Hasegawa Y (8) Kawakami R (9) Sakaguchi S (10) Hori S

Science immunology

Wei et al. used Foxp3-transduced conventional T cells as a gain-of-function probe, and identified an endogenous Foxp3+ subset that acquired Treg-like transcriptional, chromatin, and suppressive features, exclusively in vivo. Endogenous Foxp3 induction in vivo required a permissive environment created by reduced AKT-mTOR signaling and Foxp3 engagement with STAT5 and NF-κB at Foxp3 regulatory elements. Foxp3 drove a stepwise chromatin remodeling program at Foxp3-induced open chromatin regions, establishing NFκB-linked core modules shared across Treg subsets, and effector-specific modules co-regulated with AP-1.

Contributed by Shishir Pant

ABSTRACT: Regulatory T cells (T(reg) cells) express the master regulator, Foxp3, and display distinctive epigenetic landscapes ensuring T(reg) cell-specific gene expression and stable suppressive functions, yet Foxp3's contribution to this epigenetic identity remains unclear. Leveraging Foxp3-transduced conventional T cells as a gain-of-function probe in mice, we identified a previously unrecognized subset that acquires endogenous Foxp3 expression, T(reg) cell-like transcriptomic and chromatin features, and suppressive functions exclusively in vivo. These Foxp3-driven features were conserved in T(reg) cells but impaired in Foxp3-mutant T(reg)-like cells, demonstrating a Foxp3 requirement. Induction of endogenous Foxp3 expression in vivo required reduced AKT-mTOR signaling and Foxp3-dependent engagement of STAT5 and nuclear factor _B (NF-_B). Temporal chromatin profiling revealed stepwise Foxp3-driven regulatory programs, including a core program shared across T(reg) cell subsets and effector-specific programs, both associated with NF-_B activity and Foxp3 binding. Thus, Foxp3 integrates cell-intrinsic and environmental contexts to drive epigenetic programs defining T(reg) cell identities and functions, with implications for Foxp3-based therapies.

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduat

Author Info: (1) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (2) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (3) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (4) Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (5) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (6) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. (7) Department of Applied Genomics, Kazusa DNA Research Institute, Chiba 292-0818, Japan. (8) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. (9) Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan. (10) Laboratory of Immunology and Microbiology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Citation: Sci Immunol 2026 May 11:eaed2111 Epub05/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066061

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Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality

(1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

Science

Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

Contributed by Paula Hochman

(1) Altenburger LM (2) Carvoeiro DC (3) Dehio P (4) Zhou J (5) Laura C (6) Bofi I Cuadros Ë (7) Katoch M (8) KrŸger C (9) de Albuquerque JB (10) Pfenninger P (11) Magdaleno JM (12) Mehling M (13) Iannacone M (14) Gheinani AH (15) Dengjel J (16) Abe J (17) Stein JV

Science

Altenburger et al. showed that although in vitro-activated CD8+ T cells that were attached to DCs for long periods exhibited persistent TCR signaling during cell division, in lymphoid tissue, DCs and T cells detached before T cell proliferation began. DC-attached T cells were transiently unresponsive, but regained CCR7 response to CCL19/21 over 24-48hrs to reposition F-actin-promoting factor DOCK2 away from the immune synapse and allow T cell detachment, effector gene transcription, and enhanced cytolysis. Prolonged DC–T cell interaction increased PD-1 and LAG3. Detachment favored increased effector function that lasted throughout the memory phase.

Contributed by Paula Hochman

ABSTRACT: The generation of effector CD8(+) T cells (T(EFF)) requires activation of nave CCR7(+) T cells (T(N)) by dendritic cells (DCs) in lymphoid tissue. How T(N)-DC interaction duration and signal integration are controlled remains unclear. In this study, we show that lymphoid stroma-secreted CCR7 ligands limit interaction duration by progressively inducing CD8(+) T cell release from DCs. At late interaction stages, CCR7 ligands relocalize the F-actin regulator DOCK2 away from the DC interface, permitting T cell detachment, proliferation onset, and acquisition of cytotoxicity. Disruption of CCR7 signaling causes prolonged T cell-DC contacts and produces dysfunctional T(EFF) with elevated inhibitory receptors, reduced antimicrobial activity, and impaired recall responses. Stromal chemokines therefore act as critical regulators of T cell priming by DCs, preserving CD8(+) effector function during acute and memory phases.

Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribo

Author Info: (1) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (2) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (3) Department of Biomedicine, University of Basel, Basel, Switzerland. (4) Department of Biology, University of Fribourg, Fribourg, Switzerland. (5) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (6) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (7) Institute of Neuropathology, UniversitŠtsklinikum Erlangen, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg (FAU), Erlangen, Germany. (8) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. (9) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (10) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (11) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (12) Department of Biomedicine, University of Basel, Basel, Switzerland. (13) Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy. Vita-Salute San Raffaele University, Milan, Italy. Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy. (14) Functional Urology Research Group, Department for BioMedical Research DBMR, University of Bern, Bern, Switzerland. Department of Urology, Inselspital University Hospital, Bern, Switzerland. Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA. Harvard Medical School, Department of Surgery, Boston, MA, USA. Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. (15) Department of Biology, University of Fribourg, Fribourg, Switzerland. (16) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland. (17) Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland.

Citation: Science 2026 Apr 30 392:eadq2080 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42060746

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Reprogramming T cell-myeloid crosstalk overcomes immune resistance in colorectal cancer

(1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

Cell reports. Medicine

Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

Contributed by Katherine Turner

(1) Mestrallet G (2) Brown M (3) Vaninov N (4) Cho NW (5) Velazquez L (6) Ananthanarayanan A (7) Spitzer M (8) Vabret N (9) Cimen Bozkus C (10) Samstein RM (11) Bhardwaj N

Cell reports. Medicine

Mestrallet et al. focused on resistance mechanisms that limit anti-PD-1 efficacy in colorectal cancer (50% to 100% failure depending on mismatch repair status). Single-cell and spatial analysis of orthotopic and patient-derived CRC models showed anti-PD-1 increased TCR diversity and MHCI/II+ macrophage/DC interactions with T cells. Resistance correlated with immunosuppressive TREM2+ macrophages, multiple checkpoints, and IFITM+ tumors. Targeting TREM2, LAG3, CTLA-4 and PD-1 overcame resistance, and achieved up to 70% or 100% tumor clearance in MMR-proficient or MMR-deficient models, respectively, with immune memory.

Contributed by Katherine Turner

ABSTRACT: Colorectal cancer (CRC) accounts for 10% of cancer cases and is the second leading cause of cancer-related deaths. Although anti-PD-1 therapy improves outcomes, 50% of advanced mismatch repair-deficient (MMRd) and most mismatch repair-proficient (MMRp) CRC cases fail to respond. Using orthotopic and patient-derived CRC models with single-cell and spatial analyses, we show that tumor control during anti-PD-1 treatment associates with colocalization of MHC(+) C1Q(+) CXCL9(+) macrophages and TCF(+) PRF1(+) T cells. Resistance correlates with increased TIM3, LAG3, TIGIT, and PD-1 expression on T cells and enrichment of TREM2(+) macrophages in T cell-excluded regions. A combinatorial blockade targeting TREM2, LAG3, CTLA4, and PD-1 induces up to 100% tumor clearance in MMRd and >70% in MMRp models. This strategy promotes immune memory mediated by interactions among MHC(+) macrophages and CD4(+)/CD8(+)/TCF(+) T cells, while reducing immunosuppressive myeloid infiltration and T cell exhaustion, identifying key cellular programs that overcome immune escape in CRC.

Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic ad

Author Info: (1) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: guillaume.mestrallet@mssm.edu. (2) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (4) Department of Radiation Oncology and the Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA 94143, USA. (5) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (6) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (7) Department of Otolaryngology-Head and Neck Surgery and the Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143, USA. (8) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (9) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (10) The Marc and Jennifer Lipschultz Precision Immunology Institute, Department of Immunology and Immunotherapy, Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: robert.samstein@mountsinai.org. (11) Division of Hematology and Oncology, Hess Center for Science & Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: nina.bhardwaj@mssm.edu.

Citation: Cell Rep Med 2026 May 5 102786 Epub05/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42092363

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Targeted TNF Potentiates the Activity of Bispecific T-cell Engagers in Solid Tumors by Turning Cold Tumors Hot Spotlight 

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

(1) Thorhallsdottir G (2) Benz R (3) Faviana P (4) Bartoli F (5) Leonardi N (6) Sekielyk I (7) Fetriconi L (8) Cazzamalli S (9) Puca E (10) Neri D (11) Elsayed A

Cancer immunology research

As colorectal cancer immunotherapy has shown limited success, Thorhallsdottir et al. developed a dual-modality approach. L19-TNF, a TNF-based fusion protein directed to pan-tumor stromal extradomain B of fibronectin (to induce intratumoral inflammation) was combined with a CEA-targeted CD3-based T cell engager (CEAxCD3 TCE) to promote CD8+ T cell proliferation and antigen-specific cytotoxicity. In two immunocompetent models, L19-TNF plus CEAxCD3 resulted in >50% CRs, prolonged survival, and durable memory, with a tolerable safety profile. Mechanistically, the combination revealed enhanced TCE extravasation and TIME remodeling.

Contributed by Katherine Turner

ABSTRACT: Colorectal cancer remains a major global health burden and an area of urgent unmet medical need. Immunotherapy has shown limited success in colorectal cancer as most patients present with an immune-excluded, "cold" tumor microenvironment (TME). In this study, we report a dual-modality approach to treating colorectal cancer by combining the tumor necrosis factor (TNF)-based fusion protein directed to the extradomain B (EDB) of fibronectin, L19-TNF, which induces localized intratumoral inflammation and facilitates T-cell infiltration, with a CD3-based bispecific T-cell engager (TCE) targeting carcinoembryonic antigen (CEA), which mediates antigen-specific cytotoxicity. Together, these agents aim to remodel the TME, convert "cold" tumors into inflamed "hot" lesions, and broaden the therapeutic reach of immunotherapy in colorectal cancer. Immunohistochemistry confirmed coexpression of CEA and EDB across microsatellite-stable and -instable tumors. In vitro, L19-TNF in combination with a CEAxCD3 TCE significantly enhanced tumor cell killing and CD8+ T-cell proliferation. In vivo, the combination induced complete tumor regression in most animals, prolonged survival, and conferred durable protection against tumor rechallenge. Furthermore, mechanistic analyses revealed enhanced TCE extravasation, upregulated intercellular adhesion molecule 1 expression, and increased CD8+ T-cell infiltration, indicating vascular modulation and remodeling of the TME toward an inflamed "hot" phenotype. These findings confirm that targeted delivery of TNF to the TME can effectively enhance the activity of immunotherapeutic agents, such as T cell-redirecting therapies, in challenging tumor settings.

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Swit

Author Info: (1) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (2) Philochem AG, Otelfingen, Switzerland. (3) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (4) University of Pisa , Pisa, Italy. ROR: https://ror.org/03ad39j10 (5) Philochem AG, Otelfingen, Switzerland. (6) Philochem AG, Otelfingen, Switzerland. (7) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 (8) Philochem AG, Otelfingen, Switzerland. (9) Philochem AG, Otelfingen, Switzerland. Philogen SpA, Siena, Italy. (10) Philochem AG, Otelfingen, Switzerland. Swiss Federal Institute of Technology, ETH ZŸrich, Zurich, Switzerland. ROR: https://ror.org/05a28rw58 Philogen SpA, Siena, Italy. (11) Philochem AG, Otelfingen, Switzerland.

Citation: Cancer Immunol Res 2026 Apr 21 OF1-OF14 Epub04/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42012522

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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

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Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity

Spotlight 

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

(1) Geng S (2) Li Z (3) Li W (4) Liang H (5) Xu F (6) Zhang L (7) Zhang W (8) Tao S (9) Wang Y (10) Zhou Y (11) Luo S (12) Lei X (13) Li H (14) Huang WF (15) Che M (16) Liu WH (17) Huang J (18) Zhang T (19) Wang K (20) Xiao N (21) Mao K (22) Jiang Y (23) Huang H

Immunity

Geng and Li et al. performed in vivo CRISPR screens in chronic LCMV infection and identified KLF2 as a central transcriptional regulator of CX3CR1+ effector-like exhausted (Texeff-like) CD8+ T cells. KLF2 directly engaged with Texeff-like loci, including Cx3cr1, and converted CX3CR1- cells into Texeff-like cells. KLF2 loss induced a TOX-dependent terminally exhausted state with enhanced activation, proliferation, and dendritic cell colocalization. KLF2 deficiency increased antigen-specific CD8+ T cell accumulation and improved viral control across stages of chronic infection. KLF2 and PD-1 co-deletion showed superior clearance, but with severe immunopathology.

Contributed by Shishir Pant

ABSTRACT: A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krppel-like factor 2 (KLF2) as a top TF driving CX3CR1(+) effector-like exhausted cell (Tex(eff-like)) differentiation. Overexpression of KLF2 converted CX3CR1_ cells into Tex(eff-like) cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8(+) T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Tex(eff-like) program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, X

Author Info: (1) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (2) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (3) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (4) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (5) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (6) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (7) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (8) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (9) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (10) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (11) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (13) Department of Pharmacy, Xiamen Medical College, Xiamen, Fujian 361023, China. (14) Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China. (15) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (16) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (17) National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 361102, China; State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (18) State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian 351002, China. (19) School of Medicine, Xiamen University, South Xiang'an Road, Xiamen, Fujian 361102, China. (20) State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (21) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. (22) State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (23) State Key Laboratory of Cellular Stress Biology, Department of Rheumatology and Immunology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: honglinghuang@xmu.edu.cn.

Citation: Immunity 2026 Apr 27 Epub04/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42049034

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Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity Spotlight 

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

(1) Hu M (2) Liu DA (3) Wortzel I (4) Collier P (5) Nelson TM (6) Foox J (7) Zhong G (8) Tobias G (9) Asao T (10) Bojmar L (11) Kenific CM (12) Wang G (13) Caielli S (14) Wan Z (15) Qureshy S (16) Reed M (17) Piszczatowski R (18) Ravisankar P (19) Brown JA (20) Xiong S (21) Wang H (22) Lauritzen P (23) Aylon Y (24) Molina H (25) Jarnagin WR (26) Oren M (27) Stanger BZ (28) Bui J (29) Bergers G (30) No‘l A (31) Grandgenett PM (32) Hollingsworth MA (33) Tuveson D (34) Boudreau N (35) Bromberg J (36) Kelsen D (37) Jones DR (38) Santambrogio L (39) Zeng MY (40) Pascual V (41) Kim HS (42) Mason CE (43) Zhang H (44) Matei IR (45) Lyden D

Cancer cell

Hu and Liu et al. found that activated T cells secreted abundant extracellular vesicular DNA (AT-EVDNA) that was mainly from newly made genomic DNA and was rich in immune-related genes. Upon uptake of EVs by tumor cells or dendritic cells, granzyme B encapsulated in the EVs disrupted the nuclear envelope and facilitated entry of EVDNA into the nucleus, where transient expression of the EVDNA increased antigen processing and presentation machinery and cytokine production, enhancing immunogenicity. In mouse models, AT-EVs overcame immune evasion and boosted immune checkpoint blockade, supporting their potential use as an acellular immunotherapy.

Contributed by Lauren Hitchings

ABSTRACT: Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (AT(EVs)) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. AT(EV)-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EV(DNA)), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by AT(EVs) disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EV(DNA) encoding APP genes. DNase treatment removes most AT-EV(DNA), abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, AT(EVs) hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by AT(EVs) that boosts APP and anti-tumor immunity while limiting autoimmunity.

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center

Author Info: (1) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA. (2) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (3) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (4) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (5) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Systems Biology, Columbia University, New York, NY, USA. (8) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (9) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan. (10) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linkšping University, Linkšping, Sweden. (11) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (12) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (13) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (14) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (15) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (16) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (17) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (18) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (19) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (20) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (21) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (22) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (23) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (24) Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA. (25) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. (27) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Department of Pathology, University of California, San Diego, La Jolla, CA, USA. (29) Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium. (30) Laboratory of Biology of Tumor and Development, UniversitŽ de Lige, Lige, Belgium. (31) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (32) Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA. (33) Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA. (34) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. (35) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (36) Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (37) Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (38) Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA. (39) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (40) Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA. (41) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. (42) Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA. (43) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: haz2005@med.cornell.edu. (44) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: irm2224@med.cornell.edu. (45) Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: dcl2001@med.cornell.edu.

Citation: Cancer Cell 2026 Apr 30 Epub04/30/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42066762

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