Journal Articles

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

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

Cancer immunology research

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

Contributed by Lauren Hitchings

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

Cancer immunology research

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

Contributed by Lauren Hitchings

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

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

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

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

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

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The human gut microbiome primes fever after vaccination

(1) Huus KE (2) Abo H (3) Tan YH (4) Atay E (5) Rytter H (6) Keller R (7) Dauser S (8) Vu DL (9) Azad MB (10) Knight R (11) Ke A (12) Lotoski L (13) Langlois MA (14) Liu R (15) Tyakht AV (16) Youngblut N (17) Kang SM (18) Parsonnet J (19) Maier L (20) Chassaing B (21) Kremsner PG (22) Gewirtz AT (23) Esen M (24) Ley RE

Science

Huus et al. studied the impact of the SARS-CoV-2 mRNA vaccine on the gut microbiome–immune axis in 171 healthy volunteers. Participants with temperatures ≥ 0.8ºC above personal baseline upon vaccination demonstrated chronic low-grade intestinal inflammation, high expression of flagellin, and abundance of flagellated bacteria. In mice, the microbiome from these participants drove innate immune detection of flagellin by TLR5 and NLRC4, and vaccine-induced adverse reactions. Western diet and common food additives boosted the abundance of flagellated bacteria and microbial flagellin production in vitro and in vivo.

Contributed by Ute Burkhardt

(1) Huus KE (2) Abo H (3) Tan YH (4) Atay E (5) Rytter H (6) Keller R (7) Dauser S (8) Vu DL (9) Azad MB (10) Knight R (11) Ke A (12) Lotoski L (13) Langlois MA (14) Liu R (15) Tyakht AV (16) Youngblut N (17) Kang SM (18) Parsonnet J (19) Maier L (20) Chassaing B (21) Kremsner PG (22) Gewirtz AT (23) Esen M (24) Ley RE

Science

Huus et al. studied the impact of the SARS-CoV-2 mRNA vaccine on the gut microbiome–immune axis in 171 healthy volunteers. Participants with temperatures ≥ 0.8ºC above personal baseline upon vaccination demonstrated chronic low-grade intestinal inflammation, high expression of flagellin, and abundance of flagellated bacteria. In mice, the microbiome from these participants drove innate immune detection of flagellin by TLR5 and NLRC4, and vaccine-induced adverse reactions. Western diet and common food additives boosted the abundance of flagellated bacteria and microbial flagellin production in vitro and in vivo.

Contributed by Ute Burkhardt

ABSTRACT: Fever is a common adverse reaction to vaccination, contributing to vaccine hesitancy and reduced uptake. To understand variation in fever risk, we longitudinally profiled fecal microbiota, oral temperature, and serological markers in 171 healthy adults receiving Severe acute respiratory syndrome coronavirus 2 mRNA vaccines. Fever risk correlated with low-grade intestinal inflammation, increased abundance of flagellated Lachnospiraceae bacteria, and increased flagellin expression prevaccine. Microbiomes from fever-high donors triggered stronger inflammation in human intestinal organoids and drove flagellin-dependent vaccine reactions in gnotobiotic mice. Moreover, microbiome flagellin phenotypes and murine vaccine reactions were modifiable by diet. Consistent with this, human fever risk was associated with self-reported diet and metabolic markers. These findings identify the gut microbiome as a driver of vaccine-induced fever, suggesting that microbiome-targeting strategies could modulate immune tone and improve vaccine side effects.

Author Info: (1) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany.

Author Info: (1) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (2) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (3) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (4) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (5) Microbiome-Host Interactions, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (6) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (7) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (8) Mass Spectrometry Facility, Max Planck Institute for Biology TŸbingen, TŸbingen, Germany. (9) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (10) Department of Pediatrics; Center for Microbiome Innovation; Department of Computer Science and Engineering; Shu Chien-Gene Lay Department of Bioengineering; Halõcõo_lu Data Science Institute, University of California San Diego, La Jolla, CA, USA. Hong Kong University of Science and Technology Jockey Club Institute for Advanced Study, Hong Kong University of Science and Technology, Hong Kong SAR, China. (11) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (12) Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada. (13) Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, OT, Canada. (14) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (15) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (16) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. (17) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (18) Departments of Medicine and of Epidemiology and Population Health, Stanford University, Stanford, CA, USA. (19) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. Institute for Tropical Medicine, University of TŸbingen, TŸbingen, Germany. (20) Microbiome-Host Interactions, Institut Pasteur, UniversitŽ Paris CitŽ, Paris, France. (21) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. Interfaculty Institute of Microbiology and Infection Medicine, University of TŸbingen, TŸbingen, Germany. Centre de Recherches Medicales de LambarŽnŽ, LambarŽnŽ, Gabon. German Center for Infection Research (DZIF), partner site TŸbingen, TŸbingen, Germany. (22) Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. (23) Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany. Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Centre de Recherches Medicales de LambarŽnŽ, LambarŽnŽ, Gabon. (24) Department of Microbiome Science, Max Planck Institute for Biology, TŸbingen, Germany. Controlling Microbes to Fight Infections (CMFI) Cluster of Excellence, TŸbingen, Germany.

Citation: Science 2026 Oct 8 394:eaea7733 Epub10/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42848888

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

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

Cell reports. Medicine

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

Contributed by Paula Hochman

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

Cell reports. Medicine

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

Contributed by Paula Hochman

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

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

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

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

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

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Orally delivered metabolically reprogrammed probiotics for cascade-activated antitumor immunity in colorectal cancer

(1) Wang L (2) Chen Y (3) Shang Y (4) Liu J (5) Zhao M (6) Jin L (7) Shi Y (8) Zhang R (9) Chen Z (10) Yin T (11) Qiao C (12) Wang Z

Cell reports. Medicine

Wang and Chen et al. designed an oral, metabolically engineered bacterial platform (EHC) based on the probiotic E. coli strain Nissle 1917 that selectively targeted CRC cells and induced ferroptosis via depletion of intratumoral cysteine and glutathione, thus enhancing immunogenic cell death and remodeling the immunosuppressive TIME. In vivo, oral EHC suppressed orthotopic CRC tumor growth, inhibited metastatic progression, and synergized with anti-PD-1. Immune profiling revealed robust systemic and gut mucosal activation, increased numbers of mature dendritic cells, CD4+ and CD8+ T cells, and pro-inflammatory macrophages.

Contributed by Katherine Turner

(1) Wang L (2) Chen Y (3) Shang Y (4) Liu J (5) Zhao M (6) Jin L (7) Shi Y (8) Zhang R (9) Chen Z (10) Yin T (11) Qiao C (12) Wang Z

Cell reports. Medicine

Wang and Chen et al. designed an oral, metabolically engineered bacterial platform (EHC) based on the probiotic E. coli strain Nissle 1917 that selectively targeted CRC cells and induced ferroptosis via depletion of intratumoral cysteine and glutathione, thus enhancing immunogenic cell death and remodeling the immunosuppressive TIME. In vivo, oral EHC suppressed orthotopic CRC tumor growth, inhibited metastatic progression, and synergized with anti-PD-1. Immune profiling revealed robust systemic and gut mucosal activation, increased numbers of mature dendritic cells, CD4+ and CD8+ T cells, and pro-inflammatory macrophages.

Contributed by Katherine Turner

ABSTRACT: Immunotherapy for colorectal cancer (CRC) remains limited due to the inherently low tumor immunogenicity and the profoundly immunosuppressive tumor microenvironment (TME). Herein, capitalizing on the metabolic traits and anatomical accessibility of CRC, we propose a broadly applicable oral strategy based on metabolically engineered bacteria (EcN-HlpA-CGL [EHC]) for CRC immunotherapy. Mechanistically, cystathionine γ-lyase expressed by EHC disrupts redox homeostasis, triggering ferroptosis in CRC cells and thereby enhancing tumor immunogenicity. Concurrently, the intrinsic adjuvant activity of the bacteria amplifies the cancer-immunity cycle driven by immunogenic cell death and remodels the immunosuppressive TME. In vivo studies demonstrate that this orally delivered engineered bacterial platform not only suppresses the growth of orthotopic CRC tumors but also inhibits metastatic progression, indicating the induction of a potent systemic immune response. Immune profiling confirms robust systemic and gut mucosal immune activation following oral administration. Collectively, this oral metabolically engineered bacterial platform is precisely tailored to the features of CRC and offers a safe and effective immunotherapeutic strategy for this malignancy.

Author Info: (1) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (2) Engineer

Author Info: (1) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (2) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. Electronic address: chenyang@xidian.edu.cn. (3) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (4) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (5) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (6) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (7) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (8) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. (9) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. Electronic address: chenzhuang@xidian.edu.cn. (10) Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, School of Pharmacy, Guangdong Medical University, Dongguan 523808, P.R. China. Electronic address: wsyt132@163.com. (11) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. Electronic address: qiaochaoqiang@xidian.edu.cn. (12) Engineering Research Center of Molecular & Neuroimaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an 710126, P.R. China. Electronic address: wangzl@xidian.edu.cn.

Citation: Cell Rep Med 2026 Oct 12 103111 Epub10/12/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42863469

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

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

Cell reports. Medicine

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

Contributed by Alex Najibi

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

Cell reports. Medicine

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

Contributed by Alex Najibi

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

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

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

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

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

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In situ reprogramming of glioma stem cells into dendritic cell-like cells for glioblastoma immunotherapy

Spotlight 

Chunwei Tang (1,4), Weiyi Sun (1,4), Zhenmei Yang (1,4), Xiaotian Zhao (1), Jian Gao (1), Kun Han (1), Zichao Yao (1), Xianghui Dong (1), Miaoyan Liu (1), Jing Zhang (1), Zhaoyu Chen (2), Xiao Yue (1), Zhipeng Fu (1), Yan Wang (1), Maosen Han (1), Ying Liu (1), Jinxin Gao (1), Yulin Zhang (3), Xinyi Jiang (1), Chen Chen (1), Xin Wen (1), Kun Zhao (1) & Jingyi Han (1).

Nature communications

Tang, Sun, Yang, et al. reprogrammed glioma stem cells (GSCs) into cDC1-like cells in situ by administering a hydrogel to the post-op tumor cavity for slow and local delivery of CD133-targeting LNPs carrying plasmids encoding PIB (PU.1, IRF8, BATF3) and costimulatory TNFSF9. In vivo, GSCs were preferentially targeted and acquired a cDC1-like phenotype with increased antigen presentation, costimulatory signaling, and proinflammatory cytokine secretion, supporting enhanced antigen-specific effector and memory T cell responses that cleared tumor cells, improved survival and neurological outcomes, and protected against relapse and rechallenge.

Contributed by Lauren Hitchings

Chunwei Tang (1,4), Weiyi Sun (1,4), Zhenmei Yang (1,4), Xiaotian Zhao (1), Jian Gao (1), Kun Han (1), Zichao Yao (1), Xianghui Dong (1), Miaoyan Liu (1), Jing Zhang (1), Zhaoyu Chen (2), Xiao Yue (1), Zhipeng Fu (1), Yan Wang (1), Maosen Han (1), Ying Liu (1), Jinxin Gao (1), Yulin Zhang (3), Xinyi Jiang (1), Chen Chen (1), Xin Wen (1), Kun Zhao (1) & Jingyi Han (1).

Nature communications

Tang, Sun, Yang, et al. reprogrammed glioma stem cells (GSCs) into cDC1-like cells in situ by administering a hydrogel to the post-op tumor cavity for slow and local delivery of CD133-targeting LNPs carrying plasmids encoding PIB (PU.1, IRF8, BATF3) and costimulatory TNFSF9. In vivo, GSCs were preferentially targeted and acquired a cDC1-like phenotype with increased antigen presentation, costimulatory signaling, and proinflammatory cytokine secretion, supporting enhanced antigen-specific effector and memory T cell responses that cleared tumor cells, improved survival and neurological outcomes, and protected against relapse and rechallenge.

Contributed by Lauren Hitchings

ABSTRACT: Immunotherapy has revolutionized the treatment landscape for many cancers, but fails to improve the outcomes of glioblastoma multiforme (GBM), in which low tumor antigen presentation restricts the recognition and eradication of cancerous cells by immunocytes. We here report an approach to in situ reprogramming hypoimmunogenic glioblastoma stem cells (GSCs) into type 1 conventional dendritic cell (cDC1)-like cells for presenting endogenous tumor antigens and priming sustained tumoricidal T-cell responses. Specifically, our cavity-injectable nucleobase-derived lipid nanoparticle (LNP)-hydrogel superstructure efficiently delivers transcription factors (PU.1, IRF8, BATF3) and the costimulatory molecule (TNFSF9) into GSCs to induce cDC1-like reprogramming. These cDC1-like cells potentiate GBM immunogenicity, elicit robust adaptive immunity and long-term antitumor memory, thereby inhibiting tumor growth and preventing postoperative GBM relapse in mice. Collectively, this work establishes in situ tumor cell reprogramming into licensed cDC1-like cells as a therapeutic paradigm for converting immunologically “cold” tumors into a self-vaccinating immune niche with broad translational potential for hypoimmunogenic malignancy treatment.

Author Info: (1) Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory fo

Author Info: (1) Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, NMPA Key Laboratory for Technology Research and Evaluation of Drug Products and Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.(2) Shandong University of Traditional Chinese Medicine, Jinan, China. (3) Department of Neurosurgery, Qilu Hospital and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China. (4)These authors contributed equally: Chunwei Tang, Weiyi Sun, Zhenmei Yang. e-mail: xinyijiang@sdu.edu.cn; chenchen27@sdu.edu.cn; wxzbc@mail.sdu.edu.cn; kzhao2013@sdu.edu.cn; jyhantw@email.sdu.edu.cn

Citation: nat com 2026

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    Bridging innate and adaptive immunity- A bispecific SIRPαD1-αPCSK9 fusion protein reprograms macrophages for durable tumor clearance

    Spotlight 

    (1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

    Cell reports. Medicine

    Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

    Contributed by Katherine Turner

    (1) Xu C (2) Zhou K (3) Hu X (4) Nan Y (5) Sun Y (6) Dou Z (7) Zhou R (8) Xue W (9) Hu Q (10) Huang X (11) Hua X (12) Ju D (13) Zhang X

    Cell reports. Medicine

    Focused on improving macrophage-directed immunotherapy, Xu and Zhou et al. found that blocking CD47-SIRPα upregulated tumor-expressed, secreted PCSK9, resulting in macrophage MHC-1 degradation, impaired antigen presentation, and reduced CD8+T cell activation. To overcome this resistance, a bispecific SIRPαD1–anti-PCSK9 Ab fusion co-targeting CD47 and PCSK9 enhanced phagocytosis, preserved antigen cross-presentation to CD8+ T cells, reprogrammed TIME macrophages to an M1 state, and achieved potent tumor control in preclinical models. The fusion protein exhibited superior tumor targeting (via SIRPα) and had a favorable safety profile.

    Contributed by Katherine Turner

    ABSTRACT: Macrophage-directed immunotherapy, exemplified by blocking the CD47-signal regulatory protein α (SIRPα) axis, can eliminate tumors by unleashing phagocytosis. However, such approaches often fail to generate durable antitumor immunity, revealing a disconnect between innate activation and effective T cell responses. Here, we identify proprotein convertase subtilisin/kexin type 9 (PCSK9) as an adaptive resistance factor induced by macrophage checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of major histocompatibility complex class I (MHC-I) in macrophages, impairing antigen cross-presentation and CD8+ T cell priming-thus showing how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this, we engineer bispecific fusion proteins co-targeting the CD47-SIRPα checkpoint and the PCSK9-MHC-I axis, among which SIRPαD1-αPCSK9 is optimal. Dual targeting synergistically enhances phagocytosis, preserves antigen cross-presentation, and reprograms tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 activates innate and adaptive antitumor immunity, achieving potent tumor control with improved safety. These findings uncover a resistance mechanism to macrophage-centered cancer immunotherapy and establish a dual-targeting strategy bridging phagocytosis and T cell activation.

    Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue,

    Author Info: (1) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (2) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. (3) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (4) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (5) Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China. (6) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (7) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (8) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (9) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (10) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China. (11) Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address: huax@pennmedicine.upenn.edu. (12) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: dianwenju@fudan.edu.cn. (13) School of Pharmaceutical Sciences & Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China; Quzhou Fudan Institute, 108 Minjiang Avenue, Kecheng District Quzhou, Zhejiang, China. Electronic address: xuyaozhang@fudan.edu.cn.

    Citation: Cell Rep Med 2026 Oct 5 103087 Epub10/05/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42833217

    Tags:

    Tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity while minimizing immune-related adverse events

    Spotlight 

    Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

    Nature communications

    By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

    Contributed by Paula Hochman

    Zhichen Sun (1), Yifei Hu (2), Casey Moore (1,3), Baran D. Sumer (4,5), Tao Wang (6) & Jian Qiao (1,3,5).

    Nature communications

    By analyzing TGCA data and performing tumor modeling in IL-10R KO mice, Sun et al. showed that concurrent IL-10 and high IL-2 signaling correlated with improved tumor control. Combining intratumoral injections of EGFR+ tumor-targeted Cetuximab-based IL-10 and IL-2 immunocytokines boosted efficacy. Antigen-specific intratumoral CD8+ T cells were reactivated, expanded, less exhausted, and dependent on tumor cell MHC-I expression and intratumoral IL-10R+ DCs. IL-10 signaling in macrophages suppressed high-dose IL-2-induced toxicities. Combination therapy enhanced antitumor responses in ex vivo PDTF models.

    Contributed by Paula Hochman

    ABSTRACT: Tumor-targeting cytokines have emerged as a promising strategy for cancer immunotherapy, although their mechanisms of action often remain complex. In this study, we develop an approach by combining tumor-targeted IL-10 (CmAb-(IL10)2) with IL-2 (CmAb-IL2) to enhance antitumor immunity while minimizing immune-related adverse events (irAEs). We demonstrate that endogenous IL-10 plays a critical role in IL-2-mediated antitumor effects, and that the combination of CmAb-(IL10)2 and CmAb-IL2 preferentially expands less-exhausted CD8+ T cells within tumors. Mechanistically, we identify that the IL-10/IL-10 receptor (IL-10R) axis in dendritic cells (DCs) is critical for mediating the efficacy of this combination therapy by promoting intratumoral DC function. Furthermore, we show that this combination enhances antitumor immune responses in humanized female mice and ex vivo patient-derived tumor fragments models. Our findings reveal that tumor-targeted IL-10 synergizes with IL-2 to enhance antitumor immunity through the IL-10/IL-10R/DC axis within tumors, while mitigating IL-2-associated irAEs through the IL-10/IL-10R/macrophage axis. This approach offers an IL-10 based strategy to improve the efficacy of immunotherapy while reducing irAEs.

    Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Hea

    Author Info: 1 - Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 2 - Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. 3 - Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX, USA. 4 - Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, USA. 5 - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. 6 - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. e-mail: Jian.Qiao@UTSouthwestern.edu

    Citation: Nat com 2026

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      Metastasis enables immunogenicity through migrasome-mediated antigen release Spotlight 

      (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

      Nature immunology | Free PMC Article

      Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

      Contributed by Shishir Pant

      (1) Jiang D (2) He J (3) Xie R (4) Shi M (5) Liu S (6) Jia H (7) Yang B (8) Ruan X (9) Tao X (10) Xiang Y (11) Chen Y (12) Jiao L (13) Feng X (14) Yu L

      Nature immunology | Free PMC Article

      Jiang and He et al. show that during vascular migration, circulating tumor cells release antigen-enriched migrasomes, which stimulate anti-metastatic immunity. Migrasomes contained cancer-testis and mutated antigens, which were captured by macrophages and dendritic cells in secondary lymphoid organs for cross-presentation and CD8+ T cell priming. In the 4T1 tumor model, Tspan4 deletion reduced migrasome formation and increased metastasis, whereas purified migrasomes suppressed metastatic growth, prolonged survival, and synergized with anti-PD-1. Reduced Tspan4 correlated with poor survival in an invasive breast carcinoma TCGA cohort.

      Contributed by Shishir Pant

      ABSTRACT: Antigen release is a critical step in initiating antitumor immune responses, yet its regulation during metastasis is not well understood. Here we show that circulating tumor cells undergoing vascular migration produce migrasomes that serve as a metastasis-specific mechanism of antigen release. These migrasomes are enriched in tumor-associated antigens, including cancer-testis and mutated antigens, and are captured efficiently by antigen-presenting cells in secondary lymphoid organs, where they undergo cross-presentation to elicit CD8(+) T cell-mediated immune responses that constrain metastatic progression. Genetic inhibition of migrasome formation enhances metastasis, while administration of purified cancer-derived migrasomes restores immune-mediated suppression of metastatic growth. These findings show paradoxically that metastasis can enhance tumor immunogenicity through migrasome-mediated antigen release, highlighting a link between cancer dissemination and immune activation and establishing migrasomes as a distinct and potent platform for endogenous tumor antigen delivery.

      Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantat

      Author Info: (1) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. jiang-dong@zju.edu.cn. (2) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (3) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (4) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (5) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (6) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (7) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Transvascular Implantation Devices Research Institute, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. (10) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (11) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. (12) Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China. (13) Beijing Stomatological Hospital, Capital Medical University, Beijing, China. (14) State Key Laboratory of Membrane Biology, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China. liyulab@mail.tsinghua.edu.cn.

      Citation: Nat Immunol 2026 Oct 27:2088-2101 Epub09/22/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42773266

      Tags:

      Distant lymph nodes compensate for resected tumor-draining lymph nodes during cancer immunotherapy Spotlight 

      (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

      Immunity

      Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

      Contributed by Ute Burkhardt

      (1) Menzel L (2) Zhou H (3) Baish JW (4) O'Melia MJ (5) Darragh LB (6) Effiom DN (7) Specht E (8) Czapla J (9) Lei PJ (10) Rajotte JJ (11) Liu L (12) Nikmaneshi MR (13) Razavi MS (14) Vander Heiden MG (15) Ubellacker JM (16) Munn LL (17) Karam SD (18) Boland GM (19) Cohen S (20) Padera TP

      Immunity

      Menzel, Zhou et al. observed persisting responses to ICB in melanoma patients and orthotopic tumor mouse models upon complete regional tumor-draining lymph node (LN) dissection. Antigens moved through interstitial tissues, even crossing the midline, to an adjacent tissue region (lymphosome) that drains distant LNs. In these contralateral LNs, interstitial antigens were mainly presented by LN-resident cDC1s, rather than migratory DCs, and extended the ICB-mediated expansion of effector and memory T cells. In patients with head and neck cancer who were treated with neoadjuvant ICB, distant LNs became reactive in responders.

      Contributed by Ute Burkhardt

      ABSTRACT: Surgical removal of tumor-draining lymph nodes (tdLNs) is commonly performed in cancer patients. Here, we investigated whether immune checkpoint blockade (ICB) responses persist after resection of tdLNs, important sites for the initiation and maintenance of anti-cancer immunity. Melanoma patients remained responsive to programmed death 1 (PD-1) blockade after regional LN dissection. Similarly, ICB efficacy persisted after tdLN resection in orthotopic murine melanoma and mammary carcinoma models. Following tdLN removal, interstitial fluid containing soluble antigen was diverted through interstitial spaces across lymphosome boundaries to distant LNs, wherein cancer-derived antigen was acquired and presented to T cells by LN-resident type I conventional dendritic cells. These responses persisted after primary tumor resection and supported ICB-induced systemic immunity. Locoregional delivery of ICB to compensatory LNs enhanced anti-cancer responses after tdLN resection. Consistently, ICB responses in head and neck cancer patients were associated with reactive LNs at distant sites. Thus, antigen rerouting enables distant LNs to compensate for resected tdLNs and sustain anti-cancer immunity, including responses enhanced by immunotherapy.

      Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncol

      Author Info: (1) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (2) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA; Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (3) Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837, USA. (4) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (5) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (6) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (7) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (8) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (10) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (11) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (12) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (13) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (14) Koch Institute for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. (15) Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. (16) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. (17) Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. (18) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (19) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. (20) Edwin Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: tpadera@mgh.harvard.edu.

      Citation: Immunity 2026 Oct 1 Epub10/01/2026

      Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42822444

      Tags:
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