Journal Articles

KRAS-G12C inhibition-induced enrichment of MHC-Ihigh immune-active tumor cells directs immune-effector TME development to augment therapeutic efficacy

(1) Ibrahim ML (2) Foresman D (3) Zheng H (4) Liu X (5) Xie M (6) Boyle TA (7) Johnson JO (8) Rodriguez PC (9) Abate-Daga D (10) Ruffell B (11) Anderson AR (12) Haura EB (13) Yu X (14) Beg AA

Cancer immunology research

Ibrahim et al. profiled sotorasib-induced changes in syngeneic KRASG12C/Trp53−/− lung and colon carcinoma models with and without anti-PD-1. scRNAseq revealed that sotorasib reduced proliferative tumor cells and enriched MHC-Ihigh immune-active tumor cells with elevated NF-κB and STAT1 signaling, chemokine expression, and inflammatory cytokine responsiveness. Immune-active tumor cell states were associated with increased effector T cells and MHC-IIhigh macrophages, reduced regulatory myeloid cells, and enhanced anti-PD-1 efficacy. Sotorasib-resistant tumors lacked MHC-Ihigh immune-active tumor cells and associated immune remodeling.

Contributed by Shishir Pant

(1) Ibrahim ML (2) Foresman D (3) Zheng H (4) Liu X (5) Xie M (6) Boyle TA (7) Johnson JO (8) Rodriguez PC (9) Abate-Daga D (10) Ruffell B (11) Anderson AR (12) Haura EB (13) Yu X (14) Beg AA

Cancer immunology research

Ibrahim et al. profiled sotorasib-induced changes in syngeneic KRASG12C/Trp53−/− lung and colon carcinoma models with and without anti-PD-1. scRNAseq revealed that sotorasib reduced proliferative tumor cells and enriched MHC-Ihigh immune-active tumor cells with elevated NF-κB and STAT1 signaling, chemokine expression, and inflammatory cytokine responsiveness. Immune-active tumor cell states were associated with increased effector T cells and MHC-IIhigh macrophages, reduced regulatory myeloid cells, and enhanced anti-PD-1 efficacy. Sotorasib-resistant tumors lacked MHC-Ihigh immune-active tumor cells and associated immune remodeling.

Contributed by Shishir Pant

ABSTRACT: Inhibition of KRASG12C (G12Ci) has shown promising clinical activity in several cancers; however, emergence of resistance is a major limitation to long-term benefit. It remains unknown how G12Ci impacts the tumor immune microenvironment and its association with resistance. We investigated the immune modulatory impact of the G12Ci sotorasib in KrasG12C/Trp53-/- (KP) lung and colon carcinoma models. Single-cell RNA sequencing of tumors in both models demonstrated sotorasib-induced loss of proliferative tumor cells and to the enrichment of immune-active tumor cells with elevated NF-_B and interferon signaling, and elevated MHC-I expression. These changes led to an increased proportion of effector T cells and MHC-IIhi macrophages in the tumors, and a reduced proportion of regulatory myeloid cells. Furthermore, sotorasib-resistant tumors exhibited a marked reduction of MHC-Ihigh immune-active tumor cells and immune cell type changes. Enrichment of immune-active tumor cells was associated directly with sotorasib-induced activation of NF-_B and STAT1, leading to heightened responsiveness to inflammatory cytokines and to upregulation of MHC-I and chemokine expression. These findings indicate that modulation of immune-active tumor cell populations is a key mechanism associated with G12Ci therapeutic efficacy and the development of resistance.

Author Info: (1) California Northstate University Elk grove United States. ROR: https://ror.org/03h0d2228 (2) Moffitt Cancer Center Tampa United States. ROR: https://ror.org/01xf75524 (3) Moffi

Author Info: (1) California Northstate University Elk grove United States. ROR: https://ror.org/03h0d2228 (2) Moffitt Cancer Center Tampa United States. ROR: https://ror.org/01xf75524 (3) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (4) Moffitt Cancer Center United States. ROR: https://ror.org/01xf75524 (5) Moffitt Cancer Center United States. ROR: https://ror.org/01xf75524 (6) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (7) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (8) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (9) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (10) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (11) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (12) Moffitt Cancer Center Tampa, Florida United States. ROR: https://ror.org/01xf75524 (13) Moffitt Cancer Center Tampa, FL United States. ROR: https://ror.org/01xf75524 (14) H. Lee Moffitt Cancer Center & Research Institute Tampa, FL United States.

Citation: Cancer Immunol Res 2026 Sep 11 Epub09/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42726935

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Messenger RNA delivery of a dual CD25/CD122 affinity-tuned IL-2 variant prolongs exposure and potentiates antitumor T cell immunity

(1) Vormehr M (2) Kranz LM (3) Muik A (4) Fellermeier-Kopf S (5) Beck JD (6) Eisel D (7) Salomon N (8) Lui BG (9) Diekmann J (10) TŸreci (11) Sahin U

Science advances | Free PMC Article

Vormehr et al. engineered an IL-2 variant with high affinity for IL-2Rβ and low affinity for IL-2Rα delivered as mRNA encapsulated in lipid nanoparticles. Treatment of murine models showed expansion of tumor-specific CD8+ T cells with no impact on Tregs. Treatment worked synergistically with ICB and vaccination. The safety of clinically relevant doses was demonstrated in non-human primates.

(1) Vormehr M (2) Kranz LM (3) Muik A (4) Fellermeier-Kopf S (5) Beck JD (6) Eisel D (7) Salomon N (8) Lui BG (9) Diekmann J (10) TŸreci (11) Sahin U

Science advances | Free PMC Article

Vormehr et al. engineered an IL-2 variant with high affinity for IL-2Rβ and low affinity for IL-2Rα delivered as mRNA encapsulated in lipid nanoparticles. Treatment of murine models showed expansion of tumor-specific CD8+ T cells with no impact on Tregs. Treatment worked synergistically with ICB and vaccination. The safety of clinically relevant doses was demonstrated in non-human primates.

ABSTRACT: The therapeutic potential of interleukin-2 (IL-2) in cancer treatment is limited by toxicity challenges, partly due to an unfavorable pharmacokinetic profile and unintended activation of regulatory T (T(reg)) cells alongside the desired activation of CD8(+) effector T cells. To selectively stimulate CD8(+) T cells over T(reg) cells, we engineered an IL-2 variant (IL-2var) with a dual-tuned affinity profile that features reduced binding to IL-2R_ (CD25) and enhanced binding to IL-2R_ (CD122). To optimize its pharmacokinetics and facilitate tumor enrichment, the variant is fused to albumin and delivered as an mRNA encapsulated in a lipid nanoparticle (Alb-IL-2var RNA-LNP), enabling sustained systemic exposure from hepatic production upon intravenous administration. We show that Alb-IL-2var has a favorable pharmacokinetic profile and is tolerated at biologically active doses in immunocompetent mice and cynomolgus monkeys. Selective enhancement of CD8(+) T cell responses over T(reg) cells is demonstrated in vitro in human peripheral blood mononuclear cells and in vivo in mice and cynomolgus monkeys. When combined with an mRNA cancer vaccine in syngeneic subcutaneous mouse tumor models, Alb-IL-2var RNA-LNP stimulates the expansion of tumor-infiltrating and circulating tumor antigen-specific CD8(+) T cells, but not T(reg) cells. In advanced and cold syngeneic tumor models, it enhances the efficacy of radiotherapy, checkpoint inhibitors, and cancer vaccines. Combination with checkpoint inhibitors and vaccine induces profound proinflammatory conversion of cold tumors. These preclinical results validate a rational design approach to overcome the limitations of IL-2 therapy and support the clinical evaluation of Alb-IL-2var RNA-LNP for solid cancers.

Author Info: (1) BioNTech SE, Mainz, Germany. (2) BioNTech SE, Mainz, Germany. (3) BioNTech SE, Mainz, Germany. (4) BioNTech SE, Mainz, Germany. (5) BioNTech SE, Mainz, Germany. (6) BioNTech SE

Author Info: (1) BioNTech SE, Mainz, Germany. (2) BioNTech SE, Mainz, Germany. (3) BioNTech SE, Mainz, Germany. (4) BioNTech SE, Mainz, Germany. (5) BioNTech SE, Mainz, Germany. (6) BioNTech SE, Mainz, Germany. (7) TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany. (8) BioNTech SE, Mainz, Germany. (9) BioNTech SE, Mainz, Germany. (10) BioNTech SE, Mainz, Germany. HI-TRON - Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) of the DKFZ, Mainz, Germany. (11) BioNTech SE, Mainz, Germany.

Citation: Sci Adv 2026 Sep 4 12:eaeh9215 Epub09/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42696566

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Intratumoral injection of EpCAM BITE, IL-12, and GM-CSF mRNA-LNPs blocks the growth of local treated and distant untreated tumors

(1) Golubovskaya V (2) Hu L (3) Zhang S (4) Sienkiewicz J (5) Zhou H (6) Berahovich R (7) Sun J (8) Li L (9) Bodmer W (10) Wu L

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Golubovskaya et al. showed that intratumoral delivery of an anti-human EpCAM-CD3 BiTE mRNA-LNP stops growth of only directly injected EpCAM+ human tumor xenografts in immuno-incompetent mice (with i.v. human T cells). When added to the BiTE-LNPs, IL-12+GM-CSF led to control of both injected and distal tumors. Combined treatment increased the expansion of injected human T cells, expression of T cell cytolysis pathway genes, and HLA class II- and APC-associated gene expression in tumors. In blood, GM-CSF, IL-12, and the BiTE peaked between 4 and 72 hrs post-delivery, and were minimally expressed in normal tissues.

Contributed by Paula Hochman

(1) Golubovskaya V (2) Hu L (3) Zhang S (4) Sienkiewicz J (5) Zhou H (6) Berahovich R (7) Sun J (8) Li L (9) Bodmer W (10) Wu L

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Golubovskaya et al. showed that intratumoral delivery of an anti-human EpCAM-CD3 BiTE mRNA-LNP stops growth of only directly injected EpCAM+ human tumor xenografts in immuno-incompetent mice (with i.v. human T cells). When added to the BiTE-LNPs, IL-12+GM-CSF led to control of both injected and distal tumors. Combined treatment increased the expansion of injected human T cells, expression of T cell cytolysis pathway genes, and HLA class II- and APC-associated gene expression in tumors. In blood, GM-CSF, IL-12, and the BiTE peaked between 4 and 72 hrs post-delivery, and were minimally expressed in normal tissues.

Contributed by Paula Hochman

ABSTRACT: We have previously shown that a T cell engaging bispecific humanized anti-human EpCAM-CD3 antibody efficiently kills a human EpCAM positive human xenograft in an NSG partially humanized mouse injected intravenously with human T cells when the anti-EpCAM-CD3 was delivered intratumorally as an mRNA-LNP. To extend these results we tested the effects of combining the anti-human EpCAM-CD3 with various cytokines injected into a tumor on the left side of NSG mice and an uninjected tumor on the right side of the mice. Combining both IL-12 and GM-CSF with anti-EpCAM-CD3 increased the number of T cells and the expression of genes and pathways that mediated T cell-based killing in the neighborhood of both the injected and the uninjected tumor and substantial increases in the expression of HLA Class II and associated genes in both tumors. This turned the cancer cells into potentially antigen-presenting cells. The effect of combining intratumoral injection of anti-EpCAM-CD3 with cytokines IL-12 and GM-CSF on tumor growth distal to the injection site avoids serious side effects on normal tissue, and suggests this technology offers a major approach to immunotherapy for treatment of a wide range of cancers from early to severe late stages.

Author Info: (1) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (2) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (3) Promab Biotechnologies

Author Info: (1) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (2) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564. (3) Promab Biotechnologies, Richmond, CA 94564. (4) Promab Biotechnologies, Richmond, CA 94564. (5) Promab Biotechnologies, Richmond, CA 94564. (6) Promab Biotechnologies, Richmond, CA 94564. (7) Promab Biotechnologies, Richmond, CA 94564. (8) IntraAb, Richmond, CA 94564. (9) Department of Oncology, University of Oxford, Oxford OX3 7DQ, United Kingdom. ROR: https://ror.org/052gg0110 (10) Promab Biotechnologies, Richmond, CA 94564. IntraAb, Richmond, CA 94564.

Citation: Proc Natl Acad Sci U S A 2026 Sep 8 123:e2616059123 Epub09/04/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42696537

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Dendritic cell centric nanoengineering couples antigen acquisition and STING activation for cancer immunotherapy

(1) Xiang S (2) Ma S (3) Xu T (4) Yu W (5) Wang J (6) You X (7) Chai M (8) Wang X (9) Wang X (10) Zhang J (11) Liu J (12) Ren X (13) Song W (14) Qin T (15) Li S (16) Wang J

Cell reports. Medicine

Xiang et al. developed a DC-directed dual pH-gated hybrid nanoparticle (HNP) that sequentially releases αCD47 peptides in the acidic TIME to enhance antigen acquisition and subsequently cGAMP under endosomal acidification to activate intracellular STING. HNP enhanced cDC1 cross-presentation and CD8+ T cell priming, forming CXCL9-enriched cDC1 niches with increased local CD8+ T cell accumulation. HNP suppressed MC38 tumor growth and orthotopic 4T1 metastasis through Batf3-dependent cDC1s and CD8+ T cells, but not macrophages. It also enhanced human DC T cell priming and antitumor activity in a CD34+ humanized xenograft model.

Contributed by Shishir Pant

(1) Xiang S (2) Ma S (3) Xu T (4) Yu W (5) Wang J (6) You X (7) Chai M (8) Wang X (9) Wang X (10) Zhang J (11) Liu J (12) Ren X (13) Song W (14) Qin T (15) Li S (16) Wang J

Cell reports. Medicine

Xiang et al. developed a DC-directed dual pH-gated hybrid nanoparticle (HNP) that sequentially releases αCD47 peptides in the acidic TIME to enhance antigen acquisition and subsequently cGAMP under endosomal acidification to activate intracellular STING. HNP enhanced cDC1 cross-presentation and CD8+ T cell priming, forming CXCL9-enriched cDC1 niches with increased local CD8+ T cell accumulation. HNP suppressed MC38 tumor growth and orthotopic 4T1 metastasis through Batf3-dependent cDC1s and CD8+ T cells, but not macrophages. It also enhanced human DC T cell priming and antitumor activity in a CD34+ humanized xenograft model.

Contributed by Shishir Pant

ABSTRACT: Stimulator of interferon genes (STING) agonists have shown limited antitumor efficacy, in part because STING activation is not preferentially focused on dendritic cells (DCs), which specialize in cross-priming. We present a DC-centric strategy that synergistically licenses DCs by coordinating CD47-SIRP_ checkpoint relief and STING activation via dual ultra-pH-sensitive gating. Mild tumor acidity first unmasks the _CD47 cue to prime antigen acquisition. Following DC-biased uptake, a second acidic gate releases cGAMP to engage STING in antigen-bearing DCs. Functionally, efficacy requires Batf3-dependent cDC1s and CD8(+) T cells, yet is preserved after macrophage depletion. In murine models, this strategy suppresses tumor growth and metastasis with good tolerability, and it retains activity in a humanized cell-line-derived xenograft model established in NSG-SGM3 hosts, supporting activity in a partially reconstituted human immune setting. Together, this work presents a mechanism-guided combination strategy to optimize STING agonist therapy.

Author Info: (1) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009

Author Info: (1) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (2) School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (3) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (4) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (5) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (6) Tianjin Central Hospital of Obstetrics and Gynecology/Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin 300100, China. (7) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (8) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (9) State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, P.R. China. (10) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (11) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (12) School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: renxiubao@tjmuch.com. (13) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: wsong@tmu.edu.cn. (14) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: qintingting@tjmuch.com. (15) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: suxin.li@cpu.edu.cn. (16) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Haihe Laboratory of Cell Ecosystem, Tianjin 300100, China. Electronic address: jianwang03@tmu.edu.cn.

Citation: Cell Rep Med 2026 Sep 7 103025 Epub09/07/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42705236

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Breast cancer prevention by prophylactic Lalba mRNA-LNP vaccination

(1) Nishida J (2) Seehawer M (3) Rojas Jimenez E (4) Yan P (5) Bui TM (6) Foidart P (7) Muramatsu H (8) Goyette MA (9) Cai X (10) Li Z (11) Beattie MB (12) Pardi N (13) Polyak K

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Nishida et al. sought to prevent carcinogen (NMU)-induced mammary tumorigenesis in outbred Sprague-Dawley rats by targeting LALBA, a protein specifically expressed in luminal progenitor (LP) cells – the proposed cell-of-origin for breast cancer. Vaccination with N1-methylpseudouridine-modified Lalba mRNA-LNP induced antigen-specific immune responses, suppressed tumor incidence or progression, and extended tumor-free and overall survival. scRNAseq revealed a reduced frequency of proliferative LP cells upon vaccination, suggesting effective targeting of immunoreactive early mammary epithelial lesions.

Contributed by Ute Burkhardt

(1) Nishida J (2) Seehawer M (3) Rojas Jimenez E (4) Yan P (5) Bui TM (6) Foidart P (7) Muramatsu H (8) Goyette MA (9) Cai X (10) Li Z (11) Beattie MB (12) Pardi N (13) Polyak K

Proceedings of the National Academy of Sciences of the United States of America | Free PMC Article

Nishida et al. sought to prevent carcinogen (NMU)-induced mammary tumorigenesis in outbred Sprague-Dawley rats by targeting LALBA, a protein specifically expressed in luminal progenitor (LP) cells – the proposed cell-of-origin for breast cancer. Vaccination with N1-methylpseudouridine-modified Lalba mRNA-LNP induced antigen-specific immune responses, suppressed tumor incidence or progression, and extended tumor-free and overall survival. scRNAseq revealed a reduced frequency of proliferative LP cells upon vaccination, suggesting effective targeting of immunoreactive early mammary epithelial lesions.

Contributed by Ute Burkhardt

ABSTRACT: Tumor-suppressive immunity is more evident in early-stage compared to advanced tumors making it the ideal point for cancer interceptive immunotherapies. We previously described that higher peripheral T cell diversity is associated with more pronounced CD8(+) T cell infiltration in ductal carcinoma in situ of the breast, implying a close interaction between peripheral and intratumor immunity. Here, we developed lipid nanoparticle (LNP)-encapsulated messenger ribonucleic acid (mRNA) vaccines expressing the alpha-lactalbumin (LALBA) protein unique to mammary luminal progenitors (LPs) to test whether enhancing immune response by prophylactic vaccination against the putative cell-of-origin of breast cancer suppresses tumorigenesis. Vaccination of outbred Sprague-Dawley rats with N1-methylpseudouridine-modified or unmodified Lalba mRNA-LNP induced different degrees of LALBA-specific and nonspecific immune responses. The vaccination suppressed carcinogen-induced mammary tumorigenesis and improved tumor-free and overall survival without obvious toxicity in the normal mammary glands and other organs. Single-cell transcriptomic analysis revealed that vaccination decreases the frequency of a proliferative LP population in immunoreactive early epithelial hyperplasia. Overall, we provide proof of principle that prophylactic Lalba mRNA-LNP has the potential to suppress the initiation and progression of early breast neoplastic lesions.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115.

Author Info: (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (7) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (11) Acuitas Therapeutics, Vancouver, BC, Canada V6T 1Z3. (12) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94

Citation: Proc Natl Acad Sci U S A 2026 Sep 8 123:e2621855123 Epub09/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42685084

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Neutrophil-integrated syncytial CAR macrophage for cancer immunotherapy

(1) Tian T (2) Zhao S (3) Tian T (4) Li W (5) Zhang Z (6) Shi T (7) Li X (8) Liu X (9) Xu H (10) Guo Y (11) Zhang B (12) Jiang W (13) Niu B (14) Zhang Z

Nature immunology

Tian et al. fused second-generation CAR-macrophages with neutrophils, generating syncytial (S)-CAR-M with enhanced chemokine-driven solid tumor infiltration and cytotoxicity. S-CAR-Ms increased antigen presentation, generated NETs, and released ROS, killing tumor cells and enhancing phagocytosis of tumor cell debris through both scFv–antigen and PtdSer–MerTK pathways. In mice, S-CAR-Ms eliminated primary tumors and metastases, induced epitope spreading that reduced target-antigen-low cell escape, prevented recurrence, and improved survival. S-CAR-Ms also synergized with both radiotherapy and surgical resection.

Contributed by Lauren Hitchings

(1) Tian T (2) Zhao S (3) Tian T (4) Li W (5) Zhang Z (6) Shi T (7) Li X (8) Liu X (9) Xu H (10) Guo Y (11) Zhang B (12) Jiang W (13) Niu B (14) Zhang Z

Nature immunology

Tian et al. fused second-generation CAR-macrophages with neutrophils, generating syncytial (S)-CAR-M with enhanced chemokine-driven solid tumor infiltration and cytotoxicity. S-CAR-Ms increased antigen presentation, generated NETs, and released ROS, killing tumor cells and enhancing phagocytosis of tumor cell debris through both scFv–antigen and PtdSer–MerTK pathways. In mice, S-CAR-Ms eliminated primary tumors and metastases, induced epitope spreading that reduced target-antigen-low cell escape, prevented recurrence, and improved survival. S-CAR-Ms also synergized with both radiotherapy and surgical resection.

Contributed by Lauren Hitchings

ABSTRACT: The limited effectiveness of chimeric antigen receptor macrophage (CAR-M) therapy is largely due to poor tumor infiltration, reduced effector function and immune escape of target antigen-low tumors. Here we developed syncytial CAR-Ms (S-CAR-M) by fusing CAR-Ms with neutrophils. S-CAR-Ms accumulated in tumors more than conventional CAR-Ms because of chemokine-driven migration. By releasing neutrophil extracellular traps and reactive oxygen species inherited from neutrophils, S-CAR-Ms increased PtdSer exposure on tumor cells, leading to efficient phagocytosis of tumor debris through both the scFv-antigen and PtdSer-MerTK pathways. Thus, a single dose of S-CAR-Ms can reduce tumor burden, limit metastasis and prevent tumor recurrence in syngeneic and xenograft mouse models. Additionally, S-CAR-M therapy triggered antigen spreading, minimizing escape by target antigen-low tumor cells. S-CAR-Ms overcome limitations of conventional CAR-Ms toward solid tumors.

Author Info: (1) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (2) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Chi

Author Info: (1) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (2) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (3) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (4) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (5) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (6) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (7) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (8) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (9) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. (10) Department of Pharmacy, Liyuan Hospital, Huazhong University of Science and Technology, Wuhan, China. (11) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (12) Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. Central Laboratory, Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. (13) Clinical Center for Biotherapy, Department of Hepatobiliary Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province, Xiamen Key Laboratory of Biotherapy, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. Central Laboratory, Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. niu.boning@zsxmhospital.com. (14) Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn. National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn. Hubei Engineering Research Centre for Novel Drug Delivery System, Huazhong University of Science and Technology, Wuhan, China. zhipingzhang@hust.edu.cn.

Citation: Nat Immunol 2026 Aug 18 Epub08/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42613461

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Lower airway microbiome effects on responsiveness to immunotherapy in NSCLC

Fares Darawshy (1,2,3); Jun-Chieh J. Tsay (1,4,5); Elizabeth Sanchez (1,4); Dong-Min Jin (6 3); Yeji Kim (7); Qingsheng Li (1,4); Matthew Chung (8); Anton Becker (9); Imran Sulaiman (1,10,11 4); Clea Barnett (1,4); Benjamin G. Wu (1,4,5); Ray Pillai (1,4); Benjamin Kwok (1,4); Kendrew Wong (1,4 5); Matthias C. Kugler (1,4); Yonghua Li (1,4); Rosemary Schluger (1,4); Destiny Collazo (1,4 6); Yaa Kyeremateng (1,4); Alexander Bain (1,4); Miao Chang (1,4); Jamie Bessich (1); Anrew DeMaio (1 7); Isaac Laniado (1); Daniel O’Neill (12); John J. Hall (13); Jonathan Sanders (13); George Thurston (4,7 8); Marcus D. Goncalves (4,14); Ezequiel Dantas (4); Rami Vanguri (15); Kwok Kin Wong (16,9); Daniel H. Sterman (1,4); Aristotelis Tsirigos (15); James T. Morton (13); Huilin Li (7); Elodie Ghedin (8 10); Leopoldo N. Segal (1,4,17).

To investigate the contribution of the lower airway microbiome to ICB responsiveness, Darawshy et al. analyzed BAL samples from 71 NSCLC patients prior to ICB treatment and compared functional microbial and host signatures between responders and non-responders. Multi-omic analyses of BAL revealed that enriched oral commensals correlated with poor ICB response, NSCLC progression, and worse prognosis, as well as upregulation of host interferon signaling, neutrophil degranulation and mitophagy. In a lung tumor model, inoculating oral commensals increased intratumoral neutrophils and Th17 responses, and impaired ICB efficacy.

Contributed by Katherine Turner

Fares Darawshy (1,2,3); Jun-Chieh J. Tsay (1,4,5); Elizabeth Sanchez (1,4); Dong-Min Jin (6 3); Yeji Kim (7); Qingsheng Li (1,4); Matthew Chung (8); Anton Becker (9); Imran Sulaiman (1,10,11 4); Clea Barnett (1,4); Benjamin G. Wu (1,4,5); Ray Pillai (1,4); Benjamin Kwok (1,4); Kendrew Wong (1,4 5); Matthias C. Kugler (1,4); Yonghua Li (1,4); Rosemary Schluger (1,4); Destiny Collazo (1,4 6); Yaa Kyeremateng (1,4); Alexander Bain (1,4); Miao Chang (1,4); Jamie Bessich (1); Anrew DeMaio (1 7); Isaac Laniado (1); Daniel O’Neill (12); John J. Hall (13); Jonathan Sanders (13); George Thurston (4,7 8); Marcus D. Goncalves (4,14); Ezequiel Dantas (4); Rami Vanguri (15); Kwok Kin Wong (16,9); Daniel H. Sterman (1,4); Aristotelis Tsirigos (15); James T. Morton (13); Huilin Li (7); Elodie Ghedin (8 10); Leopoldo N. Segal (1,4,17).

To investigate the contribution of the lower airway microbiome to ICB responsiveness, Darawshy et al. analyzed BAL samples from 71 NSCLC patients prior to ICB treatment and compared functional microbial and host signatures between responders and non-responders. Multi-omic analyses of BAL revealed that enriched oral commensals correlated with poor ICB response, NSCLC progression, and worse prognosis, as well as upregulation of host interferon signaling, neutrophil degranulation and mitophagy. In a lung tumor model, inoculating oral commensals increased intratumoral neutrophils and Th17 responses, and impaired ICB efficacy.

Contributed by Katherine Turner

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced non-small cell lung cancer (NSCLC), yet a large proportion of patients do not respond. The lung microbiome is a key modulator of antitumor immunity, however, the functional contribution of active microbial communities and their interaction with host transcriptional programs in shaping ICI outcomes remain poorly defined. Here, we prospectively analyzed bronchoalveolar lavage (BAL) samples from 71 NSCLC patients prior to ICI initiation. We profiled the microbiome and host transcriptome in the BAL to identify microbial and host signatures in the lower airways associated with treatment response. Our data indicate that enrichment of the lower airway microbiome with oral commensals was commonly associated with disease progression and worse prognosis of patients treated with ICI. Metatranscriptomics-derived microbial clustering revealed distinct functional profiles. The microbial cluster enriched with oral commensals, which was only present among patients with poor response to ICI, had differential regulation of pathways involved in the metabolism of short- chain fatty acid, methane and pyruvate. This cluster also correlated with host immune pathways including upregulation of interferon signaling, neutrophil degranulation, and mitophagy which could contribute to the poor response to immunotherapy. A preclinical murine model of lung cancer with dysbiosis was used to examine the nature of the association further. Inoculating lung tumor-bearing mice with oral commensals increased intratumoral neutrophils and Th17 responses and impaired ICI efficacy. Our findings support the concept that microbial communities in the lower airways appear to influence tumor–immune interactions via defined metabolic– immune axes.

Author Info: (1) Division of Pulmonary and Critical Care Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA (2) The Institute of Pulmonary Medicine

Author Info: (1) Division of Pulmonary and Critical Care Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA (2) The Institute of Pulmonary Medicine, Hadassah Medical Center, Jerusalem, Israel (3) Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel (4) Department of Medicine, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA (5) Division of Pulmonary and Critical Care Medicine, VA New York Harbor Healthcare System, New York, NY, USA (6) Center for Genomics and Systems Biology, New York University, New York, New York, USA (7) Department of Population Health, New York University School of Medicine, NYU Langone Health, New York, NY, USA (8) Systems Genomics Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA (9) Department of Radiology, New York University Grossman School of Medicine, NYU Langone Health, New York, NY, USA (10) Department of Respiratory Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland (11) Department of Respiratory Medicine, Beaumont Hospital, Dublin, Ireland (12) Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Grossman School of Medicine, NY, USA (13) Gutz Analytics, Boulder CO, 80304, Rockville MD, USA (14) Department of Radiation Oncology, New York University Grossman School of Medicine, New York, New York, USA (15) Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA (16) Division of Hematology and Medical Oncology, Department of Medicine at NYU Grossman School of Medicine, NY, USA (17) Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, USA

Citation:

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    Molecular heterogeneity and clonal origin of CCR8+ effector regulatory T cells in human cancer

    Spotlight 

    Julian Swatler (1,5), Simone Puccio (1,2,5), Emanuele Voulaz (1,3), Giuseppe Marulli (1,3), Matthew Wheeler (4), Sharmila Sambanthamoorthy (4), Eloise Scamardella (1), Simona Feno (1), Sabina Testa (1), Chiara Camisaschi (1), Emilia Maria Cristina Mazza (1), Enrico Lugli (1)

    Nature communications

    Swatler, Puccio, et al. used scRNsSeq and flow cytometry to define Treg subsets and analyze heterogeneity and TCR overlap across tissues from 9 tumor types. A common intratumoral Treg signature of 88 genes was defined, and four Treg subsets were further resolved (CCR7+ quiescent; CCR8+ effector; CD161+ Th17-like; intermediate lacking strong functional markers). In NSCLC, CCR8+ effector abundance correlated negatively, and CD161+ Th17-like abundance correlated positively with relapse-free survival. CCR8+ Tregs showed strong tumor localization with clonotype expansion, strong overlap with Tregs in dLN, and some overlap with normal adjacent tissue Tregs and intratumoral Tconv.

    Contributed by Ed Fritsch

    Julian Swatler (1,5), Simone Puccio (1,2,5), Emanuele Voulaz (1,3), Giuseppe Marulli (1,3), Matthew Wheeler (4), Sharmila Sambanthamoorthy (4), Eloise Scamardella (1), Simona Feno (1), Sabina Testa (1), Chiara Camisaschi (1), Emilia Maria Cristina Mazza (1), Enrico Lugli (1)

    Nature communications

    Swatler, Puccio, et al. used scRNsSeq and flow cytometry to define Treg subsets and analyze heterogeneity and TCR overlap across tissues from 9 tumor types. A common intratumoral Treg signature of 88 genes was defined, and four Treg subsets were further resolved (CCR7+ quiescent; CCR8+ effector; CD161+ Th17-like; intermediate lacking strong functional markers). In NSCLC, CCR8+ effector abundance correlated negatively, and CD161+ Th17-like abundance correlated positively with relapse-free survival. CCR8+ Tregs showed strong tumor localization with clonotype expansion, strong overlap with Tregs in dLN, and some overlap with normal adjacent tissue Tregs and intratumoral Tconv.

    Contributed by Ed Fritsch

    ABSTRACT: CD4+CD25+FOXP3+ regulatory T cells (Treg) are highly activated in tumors and promote disease progression. Specific, universal targeting of these effector Treg cells is limited by the lack of a conserved signature across human cancers and information on their origin. Here we combine analysis of single-cell RNA-sequencing datasets with spectral flow cytometry and identify a core signature of 88 genes consistently upregulated in intratumoral Treg cells among 9 epithelial cancers. We describe 4 Treg cell subsets – CCR7+ quiescent, CCR8+ effector, CD161+ and intermediate, with distinct tissue distribution, function, differentiation trajectories and molecular drivers. By single-cell T cell receptor sequencing, we observe that protumoral, effector CCR8+ Treg cells exhibit little clonal relationship with other Treg cell subsets inside tumors, but are clonally related to Treg cells in tumor-draining lymph nodes, as well as conventional T cells in tumors. This resource provides insights for development and fine-tuning of CCR8+ Treg cell-targeting therapies in cancer.

    Author Info: 1-IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 2- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy. 3- Departm

    Author Info: 1-IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. 2- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Rozzano, Milan, Italy. 3- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. 4- Discovery Biology, Bristol Myers Squibb Company, Redwood City, California, CA, USA. 5- These authors contributed equally: Julian Swatler, Simone Puccio. e-mail: julian.swatler@humanitasresearch.it; enrico.lugli@humanitasresearch.it

    Citation: Nat com 2026

    Tags:

      Immune checkpoint blockade facilitates primary tumor rejection in a cDC1-independent manner without immunological memory acquisition

      Spotlight 

      Hitoki Arisato (1,2), Takuro Noguchi (1,3), Akihiko Shiiya (1), Yuta Toji (1), Masahiro Kashima (2), Jun Taguchi (1), Satoshi Takeuchi (1), Yasushi Shimizu (1), Hidenori Kitai (2), Kaoru Murakami (4), Jun Sakakibara-Konishi (2), Ichiro Kinoshita (5,6), Masaaki Murakami (4,7,8,9), Hirotoshi Dosaka-Akita (1), Satoshi Konno (2)

      Cancer immunology, immunotherapy

      Arisato et al. found that the LLC-2B2 subclone of LLC was universally rejected in ICB-treated WT mice and was also rejected in 36% of ICB-treated Batf3-/- mice. In Batf3-/- mice, rejection was dependent on CD8+ T cells primed by alternative XCR1- APCs, which upregulated costimulatory CD80, CD86, and CD40 in response to soluble factors secreted by LLC-2B2 cells. However, when mice that had cleared LLC-2B2 tumors were rechallenged, all WT mice rejected tumors, while most Batf3-/- mice did not, suggesting that cDC1s were important in establishing protective immune memory. Intratumoral injection of Flt3L-DCs restored protection from rechallenge.

      Contributed by Lauren Hitchings

      Hitoki Arisato (1,2), Takuro Noguchi (1,3), Akihiko Shiiya (1), Yuta Toji (1), Masahiro Kashima (2), Jun Taguchi (1), Satoshi Takeuchi (1), Yasushi Shimizu (1), Hidenori Kitai (2), Kaoru Murakami (4), Jun Sakakibara-Konishi (2), Ichiro Kinoshita (5,6), Masaaki Murakami (4,7,8,9), Hirotoshi Dosaka-Akita (1), Satoshi Konno (2)

      Cancer immunology, immunotherapy

      Arisato et al. found that the LLC-2B2 subclone of LLC was universally rejected in ICB-treated WT mice and was also rejected in 36% of ICB-treated Batf3-/- mice. In Batf3-/- mice, rejection was dependent on CD8+ T cells primed by alternative XCR1- APCs, which upregulated costimulatory CD80, CD86, and CD40 in response to soluble factors secreted by LLC-2B2 cells. However, when mice that had cleared LLC-2B2 tumors were rechallenged, all WT mice rejected tumors, while most Batf3-/- mice did not, suggesting that cDC1s were important in establishing protective immune memory. Intratumoral injection of Flt3L-DCs restored protection from rechallenge.

      Contributed by Lauren Hitchings

      ABSTRACT: Immune checkpoint blockade (ICB) provides durable therapeutic responses across multiple cancer types. Although crosstalk between T cells and conventional type 1 dendritic cells (cDC1s) is essential, the contribution of other antigen-presenting cells (APCs) to ICB-induced tumor rejection remains unclear. To address this, we show that while the majority of wild type (WT) mice rejected an immunogenic clone of Lewis lung carcinoma (LLC) following ICB, 35.7% of Batf3–/– mice, which lack the cDC1 subset, also rejected this LLC clone. ICB induced the upregulation of costimulatory markers on XCR1– APCs in the tumors and lymph nodes of Batf3–/– mice, similar to responses observed in wild-type mice. Mechanistically, conditioned culture media from LLC, but not from ICB-resistant B16F10 melanoma cells, stimulated bone marrow-derived cDC1s and cDC2s, as evidenced by the upregulation of CD40 and CD80 expression. RNA sequencing revealed that antitumor immunity-related genes were upregulated in LLC cells compared with B16F10 cells. To determine the role of cDC1-independent long-term immune memory, we rechallenged ICB-induced tumor-free mice with LLC tumors. We found that, without supplementation of cDC1s during primary rejection, Batf3–/– mice failed to spontaneously reject the rechallenged tumors. These findings demonstrate that ICB can elicit primary antitumor T cell responses against immunogenic tumors in the absence of cDC1s, whereas cDC1s are essential for the establishment of ICB-induced long-term memory. Our study underscores the importance of clinical strategies targeting both cDC1-dependent and cDC1-independent pathways to enhance the durable efficacy of ICB.

      Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medici

      Author Info: 1. Department of Medical Oncology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan 2. Department of Respiratory Medicine, Faculty of Medicine, Hokkaido University, Sapporo, Japan 3. Department of Medical Oncology, Shinshu Cancer Center, Shinshu University Hospital, Matsumoto, Japan 4. Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan 5. Department of Medical Oncology, Hokkaido University Hospital, Sapporo, Japan 6. Division of Clinical Cancer Genomics, Hokkaido University Hospital, Sapporo, Japan 7. Quantum immunology Team, Institute for Quantum Life science, National Institute for Quantum and Radiological Science and Technology (QST), Chiba, Japan 8. Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi, Japan 9. Institute for Vaccine Research and Development, Hokkaido University, Sapporo 001-0021, Japan

      Citation: Cancer immunology, immunotherapy 2026

      Tags:

        Enfortumab vedotin induces immunogenic cell death and shows enhanced preclinical antitumor activity when combined with a PD-1 inhibitor Featured  

        (1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

        Cell reports. Medicine

        Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

        (1) Olson DJ (2) Liu BA (3) Younan P (4) Blahnik-Fagan G (5) Stacey RG (6) Gosink J (7) Snead K (8) Tenn E (9) Hensley K (10) Sahetya D (11) Nesterova A (12) Zaval M (13) Cao A (14) O'Day C (15) Heiser RA (16) Lewis TS (17) Gardai SJ (18) Nakazawa T (19) Shimazaki M (20) Carosino C (21) Szeto GL (22) Sandall S

        Cell reports. Medicine

        Untangling the mechanism of enfortumab vedotin – an antibody–drug conjugate that targets Nectin-4 on cancer cells – Olson and Liu et al. showed that upon target binding, the drug is imported into the cell and transported to the lysosome, where MMAE is released, inducing direct cytotoxicity by disrupting microtubule formation and inducing ER stress and immunogenic cell death (ICD). Upon ICD, MMAE is released from the cell, killing nearby bystander cells. ICD also induces macrophage and DC activation, initiating protective antitumor immunity against both Nectin-4+ and Nectin-4- tumor cells. Enfortuman vedotin also synergized with anti-PD-1.

        ABSTRACT: Enfortumab vedotin is a Nectin-4-directed antibody-drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4-positive tumor cells, indirect bystander effect on neighboring Nectin-4-negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells results in protection against tumor rechallenge in mice, consistent with antitumor immunity. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical findings provide mechanistic hypotheses that may be relevant to the improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy.

        Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer,

        Author Info: (1) Pfizer, Inc., Bothell, WA 98021, USA. (2) Pfizer, Inc., Bothell, WA 98021, USA. (3) Seagen, Inc., Bothell, WA 98021, USA. (4) Pfizer, Inc., Bothell, WA 98021, USA. (5) Pfizer, Inc., Bothell, WA 98021, USA. (6) Pfizer, Inc., Bothell, WA 98021, USA. (7) Pfizer, Inc., Bothell, WA 98021, USA. (8) Seagen, Inc., Bothell, WA 98021, USA. (9) Pfizer, Inc., Bothell, WA 98021, USA. (10) Pfizer, Inc., Bothell, WA 98021, USA. (11) Pfizer, Inc., Bothell, WA 98021, USA. (12) Seagen, Inc., Bothell, WA 98021, USA. (13) Seagen, Inc., Bothell, WA 98021, USA. (14) Pfizer, Inc., Bothell, WA 98021, USA. (15) Pfizer, Inc., Bothell, WA 98021, USA. (16) Seagen, Inc., Bothell, WA 98021, USA. (17) Seagen, Inc., Bothell, WA 98021, USA. (18) Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. (19) Astellas Research Institute of America LLC, Northbrook, IL 60062, USA. (20) Pfizer, Inc., Bothell, WA 98021, USA. (21) Pfizer, Inc., Bothell, WA 98021, USA. (22) Pfizer, Inc., Bothell, WA 98021, USA. Electronic address: sharsti.sandall@pfizer.com.

        Citation: Cell Rep Med 2026 Sep 2 103021 Epub09/02/2026

        Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42685702

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