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

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

Journal for immunotherapy of cancer | Free PMC Article

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

Contributed by Paula Hochman

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

Journal for immunotherapy of cancer | Free PMC Article

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

Contributed by Paula Hochman

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

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

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

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

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

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

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

Cell stem cell

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

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

Cell stem cell

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

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

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

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

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

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

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

(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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    A structure-informed deep learning framework for modeling TCR-peptide-HLA interactions Spotlight 

    (1) Cao K (2) Li R (3) Stra_ar M (4) Brown EM (5) Nguyen PNU (6) Pust MM (7) Park J (8) Graham DB (9) Ashenberg O (10) Uhler C (11) Xavier RJ

    Nature communications | Free PMC Article

    Cao et al. developed StriMap – a prediction framework for modeling peptide–HLA presentation and TCR recognition as a coupled process based on physicochemical, sequence-context, and structure-informed representations that capture relevant constraints. StriMap was successfully used to screen bacterial peptides and identity candidates to activate TCRs associated with ankylosing spondylitis (AS), and a top candidate in AS was also confirmed in IBD, linking the two autoimmune diseases. In cancer, StriMap demonstrated efficacy for both TCR selection in adoptive cell therapy, and prioritizing potential neoepitopes for personalized cancer vaccines.

    Contributed by Lauren Hitchings

    (1) Cao K (2) Li R (3) Stra_ar M (4) Brown EM (5) Nguyen PNU (6) Pust MM (7) Park J (8) Graham DB (9) Ashenberg O (10) Uhler C (11) Xavier RJ

    Nature communications | Free PMC Article

    Cao et al. developed StriMap – a prediction framework for modeling peptide–HLA presentation and TCR recognition as a coupled process based on physicochemical, sequence-context, and structure-informed representations that capture relevant constraints. StriMap was successfully used to screen bacterial peptides and identity candidates to activate TCRs associated with ankylosing spondylitis (AS), and a top candidate in AS was also confirmed in IBD, linking the two autoimmune diseases. In cancer, StriMap demonstrated efficacy for both TCR selection in adoptive cell therapy, and prioritizing potential neoepitopes for personalized cancer vaccines.

    Contributed by Lauren Hitchings

    ABSTRACT: The interaction between T cell receptors (TCRs), peptides, and human leukocyte antigens (HLAs) underlies antigen-specific T cell immunity. Despite substantial advances in peptide-HLA presentation prediction, accurate modeling of coupled TCR-peptide-HLA recognition remains underdeveloped, limiting applications such as TCR and neoepitope prioritization in cancer and antigen identification in autoimmunity. Here we present StriMap, a unified framework for predicting TCR-peptide-HLA interactions by integrating physicochemical, sequence-context, and structural features at recognition interfaces. StriMap achieves state-of-the-art performance with improved generalizability and enables applications in both cancer and autoimmunity. As a case study in ankylosing spondylitis (AS), we screened 13 million peptides derived from 43,241 bacterial proteins and identified candidate molecular mimics that were experimentally validated to activate T cells expressing an AS-associated TCR. Notably, a top validated peptide was enriched in patients with inflammatory bowel disease (IBD), suggesting potential shared microbial triggers between AS and IBD. Overall, StriMap provides a generalizable framework for rational immunotherapy design and for dissecting antigenic drivers of autoimmunity.

    Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (2) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massach

    Author Info: (1) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (2) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (3) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (4) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (5) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (6) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (7) Broad Institute of MIT and Harvard, Cambridge, MA, United States. (8) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (9) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States. (10) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Massachusetts Institute of Technology, Cambridge, MA, United States. (11) Broad Institute of MIT and Harvard, Cambridge, MA, United States. Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, United States. Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, United States.

    Citation: Nat com 09/25/26

    Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41959488

    Tags:

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

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

    Cancer discovery

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

    Contributed by Ute Burkhardt

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

    Cancer discovery

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

    Contributed by Ute Burkhardt

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

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

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

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

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

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