Journal Articles

The human gut microbiome primes fever after vaccination Spotlight 

(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

Tags:

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

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

Cell reports. Medicine

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

Contributed by Paula Hochman

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

Cell reports. Medicine

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

Contributed by Paula Hochman

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

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

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

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

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

Tags:

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

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

Journal for immunotherapy of cancer | Free PMC Article

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

Contributed by Paula Hochman

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

Journal for immunotherapy of cancer | Free PMC Article

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

Contributed by Paula Hochman

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

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

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

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

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

Tags:

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

Tags:

    Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks Spotlight 

    (1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

    Cancer discovery

    Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

    Contributed by Shishir Pant

    (1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

    Cancer discovery

    Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

    Contributed by Shishir Pant

    ABSTRACT: Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

    Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86

    Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (5) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (6) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (7) Dana Farber Cancer Institute Boston United States. (8) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (9) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (10) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (11) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (12) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (13) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (14) Dana-Farber Brigham Cancer Center Boston, MA United States. ROR: https://ror.org/05rgrbr06 (15) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (16) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (17) Dana-Farber Cancer Institute United States. (18) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (19) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (20) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (21) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (22) Skyline Therapeutics Cambridge, MA United States. (23) University of Cincinnati Medical Center Cincinnati United States. ROR: https://ror.org/02p72h367 (24) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (25) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (26) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (27) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (28) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (29) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (30) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (31) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (32) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (33) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (34) Massachusetts Institute of Technology Cambridge, MA United States. ROR: https://ror.org/042nb2s44 (35) Dana-Farber Cancer Institute, Harvard University Boston, MA United States.

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

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810409

    Tags:

    IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation

    Spotlight 

    (1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

    Journal for immunotherapy of cancer | Free PMC Article

    LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

    Contributed by Shishir Pant

    (1) LaPorte KM (2) Pöder J (3) Ivanova D (4) Dalzell M (5) Serafini P (6) Villarino AV (7) Malek TR

    Journal for immunotherapy of cancer | Free PMC Article

    LaPorte et al. show that high-dose mouse IL-2/CD25 fusion protein (mIL-2/CD25) reprograms the CT26 and MC38 tumor microenvironments to favor tumor-specific CD8+ T cells over Tregs. HD mIL-2/CD25 promoted chemokine and inflammatory programs that increased intratumoral CD8+ T cell infiltration, clonal expansion, and differentiation into effector and stem-like states. In contrast, intratumoral Tregs showed impaired IL-2R signaling and effector Treg differentiation, failed to upregulate Foxp3 and CD25, and were prone to cell death. Combination with anti-PD-1 enhanced multiple tumor-specific CD8⁺ T cell effector programs and limited Treg infiltration.

    Contributed by Shishir Pant

    BACKGROUND: Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8(+) T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade. METHODS: Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8(+) T-cell differentiation is affected by different IL-2/PD-1 strategies. RESULTS: Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8(+) tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8(+) T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1(+) CD8(+) T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8(+) T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy. CONCLUSIONS: The efficient differentiation of exhausted CD8(+) T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.

    Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and

    Author Info: (1) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. (2) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (3) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (4) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (5) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (6) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA. (7) Department of Microbiology & Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA tmalek@med.miami.edu.

    Citation: J Immunother Cancer 2026 Sep 29 14: Epub09/29/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810810

    Tags:

    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:

    Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer Spotlight 

    (1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

    Science

    Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

    Contributed by Shishir Pant

    (1) Hinterleitner C (2) Barthet VJA (3) Goldberg HV (4) Vogt KC (5) Perea AM (6) Hillger LR (7) Ruiz S (8) McHugh D (9) Ho YJ (10) Chaves-Perez A (11) Skamagki M (12) Flowers S (13) Styers HC (14) Rekhtman N (15) Zhuang X (16) Dessotti Barretto G (17) Li X (18) Watson JT (19) Luan W (20) Simon J (21) Tammela T (22) Gardner R (23) Rudin CM (24) Romesser PB (25) Bott MJ (26) Filliol A (27) Heller DA (28) Lowe SW

    Science

    Hinterleitner, Barthet, and Goldberg et al. showed that senescent-like cells in fibrotic human and mouse tissues expressed P-selectin, and the team developed fucoidan-based senescence-modulating nanoparticles (SMNPs) to target these cells. SMNPs selectively depleted P-selectin+ senescent-like macrophages (Sen+MP) and reduced liver and lung fibrosis with limited toxicities. In fibrotic liver and lung tumor models, SMNPs remodeled stromal and myeloid barriers, increased DC and T cell infiltration, and improved response to ICB. P-selectin+ Sen+MP were enriched in immune-excluded human tumors and correlated with poor response to neoadjuvant ICB plus chemotherapy.

    Contributed by Shishir Pant

    ABSTRACT: Fibrotic remodeling of tissues and tumors establishes immunosuppressive microenvironments that drive organ dysfunction and, in cancer, limit response to immunotherapy. Senescent-like cells are conserved drivers of fibrosis and therapeutic targets, yet their functional heterogeneity complicates therapeutic intervention. Here, we show that P-selectin is expressed by a subset of senescent-like cells in fibrotic tissues and tumors. Leveraging fucoidan-based nanoparticles that bind P-selectin, we developed senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated states. SMNPs exerted potent antifibrotic and immunomodulatory effects while improving the therapeutic index. Mechanistically, we identified a pathogenic, immunosuppressive macrophage population as a functional target in vivo. In fibrotic tumors, niche remodeling restored immune infiltration and sensitized tumors to immune checkpoint-based therapies. These findings establish SMNPs as a generalizable strategy to target pathogenic senescent cell subsets across fibrosis and cancer.

    Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Ketter

    Author Info: (1) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. (4) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Cancer Engineering Program, Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (21) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Early Drug Development Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (28) Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

    Citation: Science 2026 Sep 24 393:eaeg4791 Epub09/24/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42784692

    Tags:

    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:

    FasL-mediated death of activated intratumoral T cells drives secondary resistance to cancer immunotherapy Spotlight 

    (1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

    Cancer immunology research

    Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

    Contributed by Alex Najibi

    (1) Qing C (2) Ghorani E (3) Foster KA (4) Uddin I (5) Beattie G (6) Costoya C (7) Galvez-Cancino F (8) Walczak H (9) Amann M (10) Peggs KS (11) Quezada SA

    Cancer immunology research

    Qing and Ghorani et al. explored mechanisms of secondary resistance (2°R) to therapy (Treg depletion via anti-CD25 mAb + GM-CSF-expressing tumor cell vaccine) in B16 tumor- bearing mice. At 2°R, the TME had reductions in activated, cycling, and effector T cells compared to at initial response, and the activated T cells showed evidence of clonal expansion, tumor-specific TCR engagement, and Fas/death receptor (DR) expression. Adding anti-FasL + repeated anti-CD25 dosing to the therapeutic regimen extended survival. In patients receiving ICB, T cell activation also correlated with DR expression, and these T cells became lost over time.

    Contributed by Alex Najibi

    ABSTRACT: Cancer progression following an initial response to immunotherapy (secondary resistance; 2°R) is a major and poorly understood problem. We treated mice bearing B16 melanoma with a combination of a regulatory T cell (Treg) depleting, non-IL-2 blocking antibody (anti-CD25NIB) and an autologous cancer cell vaccine (GVAX). The regimen yielded initial tumor shrinkage followed by 2°R; lethal progression occurred in ~90% of partially responsive (PR) tumors by days 35-50. Cell lines derived from 2°R tumors retained treatment sensitivity upon re-implantation into naïve mice, suggesting resistance was related to a loss of immune control over time. Profiling PR and 2°R tumors by flow cytometry and single-cell RNA/TCR sequencing, we found that activated CD8⁺ T cells with tumor-reactive features declined in abundance, whereas non-activated T cells and Tregs increased. Activated CD8⁺ cells showed heightened TCR stimulation, clonal expansion, and expression of apoptotic signatures and death receptors, including Fas. Their loss was not explained by lymph node accumulation or differentiation to non-activated states. These findings were validated in a clinically relevant MC38 colon carcinoma model treated with anti-PD-L1 checkpoint blockade, confirming that depletion of activated, tumor-reactive clones is a shared mechanism of 2°R across therapeutic modalities. Fas ligand (FasL) blockade reversed this loss and prolonged survival. Longitudinal transcriptional and tissue staining data from human checkpoint blockade studies similarly indicated that activated T cells decline in abundance over time and at 2°R. These findings implicate death of activated T cells as a mechanism of 2°R and suggest Fas-FasL blockade may extend response durability.

    Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer In

    Author Info: (1) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (2) University College London Cancer Institute, London United Kingdom. (3) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (4) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (5) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (6) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (7) University of Oxford Oxford United Kingdom. ROR: https://ror.org/052gg0110 (8) University College London London United Kingdom. ROR: https://ror.org/02jx3x895 (9) Roche (Switzerland) Schlieren Switzerland. ROR: https://ror.org/00by1q217 (10) University College London Cancer Institute, London United Kingdom. (11) University College London London United Kingdom. ROR: https://ror.org/02jx3x895

    Citation: Cancer Immunol Res 2026 Sep 15 Epub09/15/2026

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42743199

    Tags:
    Close Modal

    Subscribe to our mailing list

    GDPR Marketing Permissions

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

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

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

    Close Modal

    Small change for you. Big change for us!

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

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

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

    All transactions are securely made through Stripe.