Journal Articles

Tumor-to-dendritic cell reprogramming induces immunogenic lymphoid structures across cancers

(1) Ascic E (2) Chatelain C (3) Fontanari G (4) Pérez Bucio C (5) Zhang L (6) Thrasyvoulou M (7) Karali V (8) Ballocci T (9) de Rosa Torres M (10) Rabreau S (11) Hampton K (12) Lauss M (13) Phung B (14) Akerström F (15) Sundaramurthy AK (16) Catena X (17) Fan C (18) Jonathan S (19) Darabi A (20) Bengzon J (21) Rosa FF (22) Jönsson GB (23) Kurochkin I (24) Pereira CF

Immunity

Ascic, Chatelain, et al. investigated TLSs initiated in various tumor models after PIB-transduction of tumor cells into cDC1s. Immunogenic TLSs formed in tumors and were associated with improved outcomes, immune memory, and, in some cases, synergized with ICB. TLS formation was dependent on T and B cells, and on MHC-I and CD40 signaling.

(1) Ascic E (2) Chatelain C (3) Fontanari G (4) Pérez Bucio C (5) Zhang L (6) Thrasyvoulou M (7) Karali V (8) Ballocci T (9) de Rosa Torres M (10) Rabreau S (11) Hampton K (12) Lauss M (13) Phung B (14) Akerström F (15) Sundaramurthy AK (16) Catena X (17) Fan C (18) Jonathan S (19) Darabi A (20) Bengzon J (21) Rosa FF (22) Jönsson GB (23) Kurochkin I (24) Pereira CF

Immunity

Ascic, Chatelain, et al. investigated TLSs initiated in various tumor models after PIB-transduction of tumor cells into cDC1s. Immunogenic TLSs formed in tumors and were associated with improved outcomes, immune memory, and, in some cases, synergized with ICB. TLS formation was dependent on T and B cells, and on MHC-I and CD40 signaling.

ABSTRACT: Tertiary lymphoid structures (TLSs) in tumors are associated with improved responses to immunotherapy. Here, we examined the impact of type 1 conventional dendritic cells (cDC1s) in TLS formation. Reprogrammed tumor cells into cDC1-like cells remodeled the tumor microenvironment and induced immunogenic TLSs (imgTLSs) across melanoma, colon, bladder, breast, and pancreatic cancer models with distinct genetic backgrounds. cDC1-like cells activated lymphotoxin, TNF, and interferon programs and engaged early with T cells through MHC class I and CD40 signaling to induce imgTLSs containing BCL6(+) germinal centers, independently of endogenous cDC1s. Intratumoral positioning shaped distinct cDC1-like cell states, with DC-LAMP(+) CCR7(+) migratory cDC1s nucleating niches enriched in CD4(+), CD8(+) T cells, and B cells in mouse and human tumors. ImgTLSs sustained B and T cell responses and promoted systemic immunity through expansion of shared clonotypes in distant, untreated tumors. Our findings outline the spatial organization, signaling programs and interactions of cDC1-like cells that initiate intratumoral lymphoid structures and establish cellular reprogramming as a strategy toward overcoming resistance to immunotherapy.

Author Info: (1) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Lab

Author Info: (1) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (2) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (3) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (4) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (5) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (6) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (7) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (8) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (9) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (10) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (11) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (12) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (13) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (14) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden; Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (15) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (16) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (17) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (18) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (19) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (20) Department of Clinical Sciences, Lund University, SkŒne university hospital, Lund, Sweden. (21) Asgard Therapeutics AB, Medicon Village, Lund, Sweden. (22) Department of Clinical Sciences, Division of Oncology and Pathology, Lund University Cancer Center, Lund University, Lund, Sweden. (23) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden. (24) Division of Immuno-Oncology, Lund Stem Cell Center, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Science for Life Laboratory (SciLifeLab), Lund University, Lund, Sweden; Asgard Therapeutics AB, Medicon Village, Lund, Sweden; CNC - Centre for Neuroscience and Cell Biology, University of Coimbra, Largo Marqus do Pombal, Coimbra, Portugal; CiBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal. Electronic address: filipe.pereira@med.lu.se.

Citation: Immunity 2026 Nov 4 Epub11/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42982037

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Perivascular macrophages restrict CXCR4-dependent accumulation of stem-like CD8+ T cells in tumors and limit chemotherapy efficacy

(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

Cell stem cell

Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

Contributed by Paula Hochman

(1) Cheung TS (2) Sarkar J (3) Yang DD (4) Feehan KT (5) Lovell WPM (6) Bahri M (7) Boad J (8) Macmorland W (9) Weitsman G (10) Caipa Garcia AL (11) Anstee JE (12) Bornemann L (13) Jones B (14) Kallayil AM (15) Dhami P (16) Ng T (17) Arnold JN

Cell stem cell

Cheung et al. showed that the onset of antitumor immunity in murine breast cancer models following cytotoxic chemotherapy (CCT) and loss of perivascular (Pv) TAM-derived heme oxygenase-1 activity was characterized by tumoral accumulation and differentiation of clonally diverse stem-like TCF1+PD-1+CD8+ T cells to tumor-reactive TCF1-CD8+ effector T cells. Their accumulation in the TIME was CXCR4-dependent and associated with CCT-induced expansion of proliferating Pv CXCL12+CD34+ cancer-associated fibroblasts. In human breast cancer, more favorable clinical outcomes post-CCT were associated with a high stem-like CD8+ T cell gene signature.

Contributed by Paula Hochman

ABSTRACT: The perivascular (Pv) niche coordinates immune-stromal interactions that facilitate cancer progression. Pharmacological inhibition or genetic inactivation of the enzyme heme oxygenase-1 (HO-1) in LYVE-1(+) Pv tumor-associated macrophages (PvTAMs) synergizes with cytotoxic chemotherapy (CCT) to achieve immunological tumor control in murine breast cancer models. We investigated the tumor microenvironment (TME) during the transition to immunological control and identified an increase in stem-like TCF1(+)PD-1(+)CD8(+) T cells and enrichment of tumor-selective effector T cells. Stem-like CD8(+) T cells were clonally diverse and rapidly acquired a TCF1(-) differentiated phenotype in the TME. Their tumor accumulation depended on CXCR4 and was associated with a treatment-induced expansion of proliferating CXCL12(+)CD34(+) Pv cancer-associated fibroblasts (CAFs). In human breast cancer, greater abundance of the stem-like CD8(+) T cell program was associated with improved outcomes following CCT. These findings identify PvTAM HO-1 activity as a regulator of a stromal-stem-like T cell axis that limits chemotherapy efficacy and anti-tumor immunity.

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL

Author Info: (1) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (2) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (3) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (4) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (5) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (6) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (7) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (8) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (9) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (10) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (11) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (12) Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Stra§e 68, 51429 Bergisch Gladbach, Germany. (13) Genome Centre, Blizard Institute, Queen Mary University of London, London E1 2AT, UK. (14) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (15) Genomics Research Platform, Advanced Therapies Centre, Guy's Hospital, King's College London, London SE1 9RT, UK. (16) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. (17) School of Cancer and Pharmaceutical Sciences, King's College London, London SE1 1UL, UK. Electronic address: james.arnold@kcl.ac.uk.

Citation: Cell Stem Cell 2026 Nov 4 Epub11/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42982040

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Personalized neoantigen-targeting cancer vaccines in ovarian cancer: a phase 1 trial Featured  

(1) Sellars MC (2) Frank JA (3) Shim B (4) Vanasse A (5) Liu R (6) Forman C (7) Tu CR (8) Tabata KK (9) Kowelewski A (10) Cheng SC (11) Song C (12) Xiong K (13) Jain P (14) Crnjac A (15) Sax HE (16) Chea V (17) Lu W (18) Janes JT 3rd (19) Rickles-Young M (20) Sud A (21) Sarolkar S (22) Hayes M (23) Olive O (24) Greenslade H (25) Cibulskis C (26) Hacohen N (27) Fritsch EF (28) Li S (29) Livak KJ (30) Tayob N (31) Stover EH (32) Krasner C (33) Porter R (34) Matulonis U (35) Getz G (36) Oliveira G (37) Ott PA (38) Simon JM (39) Adalsteinsson VA (40) Keskin DB (41) Konstantinopoulos PA (42) Wu CJ

Nature medicine

In a phase 1 clinical trial, Sellars et al. evaluated the adjuvant use of personalized cancer vaccines in combination with nivolumab in patients with high-grade ovarian cancer treated with standard-of-care platinum-based chemotherapy. Treatment was feasible and well tolerated, with evidence of vaccine-induced T cell responses and antitumor immunity. Immune escape through several mechanisms was also observed.

(1) Sellars MC (2) Frank JA (3) Shim B (4) Vanasse A (5) Liu R (6) Forman C (7) Tu CR (8) Tabata KK (9) Kowelewski A (10) Cheng SC (11) Song C (12) Xiong K (13) Jain P (14) Crnjac A (15) Sax HE (16) Chea V (17) Lu W (18) Janes JT 3rd (19) Rickles-Young M (20) Sud A (21) Sarolkar S (22) Hayes M (23) Olive O (24) Greenslade H (25) Cibulskis C (26) Hacohen N (27) Fritsch EF (28) Li S (29) Livak KJ (30) Tayob N (31) Stover EH (32) Krasner C (33) Porter R (34) Matulonis U (35) Getz G (36) Oliveira G (37) Ott PA (38) Simon JM (39) Adalsteinsson VA (40) Keskin DB (41) Konstantinopoulos PA (42) Wu CJ

Nature medicine

In a phase 1 clinical trial, Sellars et al. evaluated the adjuvant use of personalized cancer vaccines in combination with nivolumab in patients with high-grade ovarian cancer treated with standard-of-care platinum-based chemotherapy. Treatment was feasible and well tolerated, with evidence of vaccine-induced T cell responses and antitumor immunity. Immune escape through several mechanisms was also observed.

ABSTRACT: Personalized neoantigen-targeting cancer vaccines in the adjuvant setting are of increasing interest across malignancies. Here we report the results of a phase 1 clinical trial testing the feasibility and safety of personalized neoantigen-targeting cancer vaccines for high-grade epithelial ovarian cancer. 'NeoVax' consisted of pools of synthetic long peptides targeting patient-specific neoantigens admixed with the immunostimulant poly-ICLC, was combined with delayed administration of anti-PD-1 antibody, and was tested in ten patients (one newly diagnosed patient (Cohort A) and nine patients at first recurrence (Cohort B)) with platinum-sensitive ovarian cancer following standard-of-care platinum doublet chemotherapy. Nine of 12 evaluable Cohort B patients were vaccinated (75%, 90% CI 47-93%) and 1 of 9 Cohort A patients (11%, 90% CI 0.6-43%). No unexpected safety signals were encountered and no patients discontinued treatment due to toxicity. Across patients, >70% selected targets remained detectable by noninvasive cell-free DNA analysis despite a median of 6.5 months from the time of diagnostic biopsy to vaccine administration, during which, patients received standard-of-care chemotherapy. Biomarker analysis was suggestive of biologic activity of the vaccine in six of ten patients and this was associated with broader tumor and vaccine-specific immune responses in blood and tumor following vaccination. Resistant tumor clones reflected diverse mechanisms affecting antigen presentation, indicative of immune-selective pressure exerted by vaccination. Overall, the interplay between the repertoire of antigens presented by the tumor and the breadth of induced immunity seemed to dictate clinical efficacy following vaccination. ClinicalTrials.gov identifier: NCT04024878 .

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer I

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (3) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (4) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (5) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (7) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (11) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (16) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (17) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (18) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (19) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (20) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (21) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (22) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (23) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (24) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (25) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (26) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (28) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (29) Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. (30) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (31) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (32) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (33) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (34) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (35) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. Department of Pathology, Harvard Medical School, Boston, MA, USA. (36) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (37) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (38) Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. (39) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (40) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. Department of Medical Education and Biomedical Sciences, Methodist University CFVH School of Medicine, Fayetteville, NC, USA. (41) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. Mellen and Eisenson Family Center for BRCA and Related Genes, Dana-Farber Cancer Institute, Boston, MA, USA. Panogiotis_Konstantinopoulos@dfci.harvard.edu. (42) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu. Harvard Medical School, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Catherine_Wu@dfci.harvard.edu. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Catherine_Wu@dfci.harvard.edu.

Citation: Nat Med 2026 Oct 14 Epub10/14/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42875558

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Targeting MDA5 induces immunogenic cell death and promotes anti-tumor immunity

Spotlight 

Zhitong Niu, Bing Cheng, Yue Jiang, Yingzhen Weng, Qian Xiao, Guojie Long, Chaoying Wei, Qiufeng Liu, Jinxin Chen, Xiaofeng Wen, Yufeng Chen, Panpan Wang, Yan Huang, Jing Tan, Weidong Pan, Ronghua Zhang, Qiang Yu, Xiaojian Wu & Wenyu Wang

Nature communications

Niu and Cheng et al. found that the RNA sensor MDA5 promoted tumor immune evasion by suppressing the unfolded protein response and the release of DAMPs associated with immunogenic cell death (ICD). Targeting MDA5 in murine tumors enhanced ICD as well as DC antigen uptake and cross-talk with T cells, resulting in increased T cell activation, tumor infiltration, effector functions, and memory. MDA5 depletion also primed the ASK1-JNK/P38 pathway in tumors, increasing vulnerability to TNFα and IFNγ. In patient data, MDA5 was upregulated in cancer, and high pre-treatment MDA5 predicted poor survival and resistance to ICB across multiple cancers.

Contributed by Lauren Hitchings

Zhitong Niu, Bing Cheng, Yue Jiang, Yingzhen Weng, Qian Xiao, Guojie Long, Chaoying Wei, Qiufeng Liu, Jinxin Chen, Xiaofeng Wen, Yufeng Chen, Panpan Wang, Yan Huang, Jing Tan, Weidong Pan, Ronghua Zhang, Qiang Yu, Xiaojian Wu & Wenyu Wang

Nature communications

Niu and Cheng et al. found that the RNA sensor MDA5 promoted tumor immune evasion by suppressing the unfolded protein response and the release of DAMPs associated with immunogenic cell death (ICD). Targeting MDA5 in murine tumors enhanced ICD as well as DC antigen uptake and cross-talk with T cells, resulting in increased T cell activation, tumor infiltration, effector functions, and memory. MDA5 depletion also primed the ASK1-JNK/P38 pathway in tumors, increasing vulnerability to TNFα and IFNγ. In patient data, MDA5 was upregulated in cancer, and high pre-treatment MDA5 predicted poor survival and resistance to ICB across multiple cancers.

Contributed by Lauren Hitchings

ABSTRACT: Identifying targets to enhance tumor immunity is an urgent need. Although nucleic acid sensors play critical roles in promoting tumor immune clearance, their exceptionally low mutation rate in cancers suggests potential unexplored roles in tumor progression. Here, we demonstrate that the RNA sensor melanoma differentiation-associated protein 5 (MDA5) promotes immune evasion, and its high expression is strongly predictive of poor survival and resistance to immune checkpoint blockade (ICB) therapy in patients. Targeting MDA5 reshapes the tumor microenvironment, strengthening immune memory responses and enhancing effector CD8⁺ T cell activity in preclinical models in female mice. Mechanistically, MDA5 deficiency triggers unfolded protein response driven immunogenic cell death through induction of damage-associated molecular patterns, leading to enhanced dendritic cell-mediated antigen engulfment and T cell activation. Additionally, MDA5 loss primes the ASK1-JNK/P38 signaling pathway, sensitizing tumor cells to TNF-α/IFN-γ, further amplifying this process. Consequently, targeting MDA5 enhances the efficacy of ICB therapy across multiple cancer types, positioning it as a promising therapeutic target.

Author Info: Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Zhitong Niu, Bing Cheng,

Author Info: Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Zhitong Niu, Bing Cheng, Yue Jiang, Yingzhen Weng, Qian Xiao, Chaoying Wei, Qiufeng Liu, Jinxin Chen, Xiaojian Wu & Wenyu WangGuangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Zhitong Niu, Bing Cheng, Yue Jiang, Yingzhen Weng, Qian Xiao, Chaoying Wei, Qiufeng Liu, Jinxin Chen, Xiaojian Wu & Wenyu WangBiomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Zhitong Niu, Bing Cheng, Yue Jiang, Yingzhen Weng, Qian Xiao, Guojie Long, Chaoying Wei, Qiufeng Liu, Jinxin Chen, Xiaofeng Wen, Yufeng Chen, Yan Huang, Weidong Pan, Xiaojian Wu & Wenyu WangDepartment of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Guojie Long, Xiaofeng Wen, Yufeng Chen, Weidong Pan & Xiaojian WuThe First Affiliated Hospital of Jinan University, Guangzhou, 510630, China Panpan WangDepartment of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China Yan HuangState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China Jing TanLaboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, 168583, Singapore Jing TanHainan Academy of Medical Science, Hainan Medical University, Haikou, 571199, China Jing TanPharmacy college, Jinan University, Guangzhou, 510632, China Ronghua ZhangCancer research institute, Jinan University, Guangzhou, 510632, China Ronghua ZhangGenome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, 138672, Singapore Qiang YuDepartment of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore Qiang YuCancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore Qiang Yu

Citation: Nat commun (2026)

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    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

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