Journal Articles

Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma Spotlight 

(1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

Journal for immunotherapy of cancer | Free PMC Article

Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

Contributed by Alex Najibi

(1) Li HL (2) Charmsaz S (3) Reisman BJ (4) Hayek F (5) Brancati M (6) Leatherman JM (7) Pazzi C (8) Lee RP (9) Zhao X (10) Christenson E (11) Arif W (12) Hernandez J (13) Ellis C (14) Gross NE (15) Thoburn C (16) Chandler GS (17) Mohindra R (18) Bansal S (19) Tang L (20) Guha A (21) Dang CV (22) Zaidi N (23) Jaffee EM (24) Laheru D (25) Zabransky DJ (26) Barretti M (27) Ho WJ (28) Yarchoan M (29) Nakazawa M

Journal for immunotherapy of cancer | Free PMC Article

Among a retrospective cohort of 84 HCC patients treated with ICB, those who received their first ICB dose in the morning (prior to 12 noon) had increased PFS (and a trend in OS) compared to those receiving a first dose in the afternoon. The timing of subsequent doses did not have a similar stratifying effect, and morning dosing did not raise the rate of irAEs. Comparing baseline and early on-treatment blood samples, Li et al. found that patients first receiving ICB in the morning had diminished induction of certain cytokines (IL-6, IL-1B, VEGF-A, and IL-21) and a greater expansion of cytotoxic CD8+ Tcm cells, compared to those receiving an afternoon dose.

Contributed by Alex Najibi

BACKGROUND: Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown. METHODS: We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay. RESULTS: Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T_cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T_cells (p=0.06). CONCLUSIONS: Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (2) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (3) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (4) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (5) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (6) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (7) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (8) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. (9) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (10) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (11) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (12) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (13) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (14) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (15) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (16) F Hoffmann-La Roche Ltd, Basel, Switzerland. (17) F Hoffmann-La Roche Ltd, Basel, Switzerland. Genentech Inc, South San Francisco, California, USA. (18) Genentech Inc, South San Francisco, California, USA. (19) Genentech Inc, South San Francisco, California, USA. (20) Genentech Inc, South San Francisco, California, USA. (21) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. Ludwig Institute for Cancer Research, Baltimore, Maryland, USA. (22) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (23) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (24) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (25) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (26) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (27) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. (28) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu. (29) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA mark.yarchoan@jhmi.edu mnakaza2@jhmi.edu.

Citation: J Immunother Cancer 2026 Apr 21 14: Epub04/21/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42014205

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Selective depletion of virus-specific CD8 T cells from the liver after PD-1 therapy with Fc-intact antibody during chronic infection Spotlight 

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

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

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

(1) Hashimoto M (2) Nasti TH (3) Jin HT (4) Bu M (5) Araki K (6) Lee J (7) Valanparambil RM (8) Akhtar A (9) Khan MA (10) Peng Z (11) Hu Y (12) McManus DT (13) Bahhar I (14) Wieland A (15) Davis CW (16) Ramalingam SS (17) Sharpe AH (18) Ravetch JV (19) Freeman GJ (20) Ahmed R

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

Hashimoto et al. demonstrated that the Fc region of species-matched mouse anti-mouse PD-1 antibodies engaged with activating FcγRIII and triggered phagocytosis of LCMV-specific CD8+ T cells in the context of chronic infection. T cell depletion occurred preferentially in the liver, and impaired viral control in this organ. The effect was not limited to a specific antibody clone or IgG subclass, and was affected by mutations in the Fc region (no binding to FcγR) or afucosylation (enhanced FcγR affinity), and the presence of immune complexes. In a CT26 tumor model, the Fc-wild-type antibody depleted intratumoral PD1+ tumor-specific CD8+ T cells and accelerated tumor growth.

Contributed by Ute Burkhardt

ABSTRACT: Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (Fc_R) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block Fc_R interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating Fc_R III or inhibitory Fc_R IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating Fc_R III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, Fc_R-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.

Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. CHA Biotech, CHA Bio Complex, Seongnam-si, Gyeonggi-do 13488, Republic of Korea. (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. Medical Scientist Training Program, UCSF Graduate Division, School of Medicine, University of California, San Francisco, CA 94143. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Division of Infectious Diseases, Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Viral Immunology Laboratory, Institut Pasteur Korea, Seongnam 13488, Republic of Korea. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (8) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (9) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Immunology Laboratory, Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar 140001, India. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (13) Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (14) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Otolaryngology, Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210. (15) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. (16) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322. (17) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA (18) Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. Department of Medicine, Harvard Medical School, Boston, MA 02115. (20) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322.

Citation: Proc Natl Acad Sci U S A 2026 Apr 14 123:e2427192123 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41950082

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Intratumoral Treg cell ablation elicits NK cell-mediated control of CD8 T cell-resistant tumors

Featured  

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

(1) Zhang C (2) Chien C (3) Jurgaityt_ E (4) Sakiyama K (5) Bockman A (6) Jo Y (7) Lee S (8) Silveria S (9) Andrews E (10) Mende A (11) Zhang L (12) Garcia KC (13) Wagner A (14) DuPage M (15) Raulet D

Science immunology

Zhang et al. found that intratumoral depletion of Tregs elicited potent antitumor NK cell responses that controlled MHC-I-deficient and even MHC-I-proficient cancers expressing sufficient NKG2D ligands. This effect was dependent on cDC2-mediated activation of CD4+ T cells and their subsequent production of IL-2, which directly enhanced NK cell activation and cytotoxic potential. Antibody-mediated depletion of intratumoral Tregs or administration of exogenous IL-2 had similar effects.

ABSTRACT: Cancer cells frequently lose major histocompatibility complex class I (MHC I) to evade CD8 T cell recognition. Natural killer (NK) cells are poised to target MHC I-deficient cancer cells, but MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here, we show that selective intratumoral (IT) ablation of regulatory T cells (T(reg) cells) elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I(+) cancers that expressed NKG2D ligands. T(reg) cells controlled the activation, maturation, and antitumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, depletion of IT-T(reg) cells relieved the inhibition of cDC2-dependent induction of IL-2 production by conventional CD4 T cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT-T(reg) cells similarly empowered NK cell-dependent tumor control. These findings expand the breadth of T(reg) cell-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that therapeutic targeting of T(reg) cells in tumors can control CD8 T cell-resistant cancers.

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electric

Author Info: (1) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (6) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (7) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (8) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (9) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (10) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (11) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (12) Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University School of Medicine, Palo Alto, CA 94305, USA. (13) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, CA 94720, USA. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (14) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (15) Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Citation: Sci Immunol 2026 Apr 10 11:eadx4411 Epub04/10/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41961946

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Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumor microenvironment Featured  

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

(1) Maltez VI (2) Arora C (3) Gribbin KP (4) Caruso B (5) Haerr ME (6) Sor R (7) Lian Q (8) Blise KE (9) Sivagnanam S (10) Sears RC (11) Coussens LM (12) Vonderheide RH (13) Germain RN (14) Byrne KT

Immunity

Maltez et al. reported that in combination with anti-PD-1 and anti-CTLA-4, treatment with agonist anti-CD40 induced spatial reorganization of Tregs within PDAC tumor microenvironments, and supported the conversion of conventional Tregs into “ExTregs”. These effects were dependent on cDC1s through Cxcl9/Cxcr3-mediated recruitment, IFNγ and IL-12 stimulation, and direct TCR–MHC-II interactions with Tregs in the tumor periphery. In Tregs, these interactions activated nuclear translocation of NFAT1, leading to Foxp3 loss and acquisition of Th1-like features, including Tbet and IFNγ expression. Observations in patient samples were consistent with this pattern, and loss of Tregs was associated with longer disease-free survival.

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), agonistic anti-CD40 (αCD40) reduces frequencies of intratumoral regulatory T (Treg) cells despite a lack of CD40 expression on Treg cells. Here, we leveraged spatiotemporal imaging and lineage tracing approaches to examine intratumoral Treg cell fate in a mouse model of PDAC, where immune checkpoint blockade (ICB) (αPD-1 + αCTLA-4) combined with αCD40 controls tumor growth. Intratumoral Foxp3+ Treg cell numbers collapsed upon treatment, dependent on CD40-activated dendritic cells (DCs) and induction of interleukin (IL)-12 and interferon (IFN)-γ. This reduction corresponded with cellular alterations; Treg cells acquired an "ExTreg" phenotype characterized by loss of Foxp3 expression and acquisition of T helper 1 (Th1)-like features (Tbet+IFN-γ+). αCD40 promoted a spatially reorganized tumor microenvironment (TME), with Cxcr3⁺ Treg and ExTreg cells localized to the tumor periphery with Cxcl9-expressing DCs. Through in situ analyses of T cell receptor (TCR) signaling, we found that ExTreg cells had the highest antigen-driven activation among tumor-infiltrating T cells. Reprogramming of intratumoral Treg cells into Th1-like effectors reveals plasticity and an anti-tumor capacity of these cells.

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Beth

Author Info: (1) Postdoctoral Research Associate Training (PRAT) Program Fellow, NIGMS, NIH, Bethesda, MD, USA; Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (2) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (4) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA. (5) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; Graduate Program in Biomedical Sciences, Oregon Health and Science University, Portland, OR, USA. (6) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA. (8) Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (9) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (10) The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA. (11) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA. (12) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. (13) Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA; Center for Advanced Tissue Imaging (CAT-I), NIAID and NCI, NIH, Bethesda, MD, USA. Electronic address: rgermain@niaid.nih.gov. (14) Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; The Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, Portland, OR, USA; Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: byrneka@ohsu.edu.

Citation: Immunity 2026 Apr 14 59:1058-1074.e7 Epub04/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41932343

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PD-1 antibody-bound progenitor-exhausted CD8+ T cells in lymph nodes boost PD-1-blockade anti-tumor immunity in gastrointestinal cancer

Spotlight 

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

(1) Nose Y (2) Yasumizu Y (3) Saito T (4) Nakamura Y (5) Jinushi K (6) Fujikawa K (7) Momose K (8) Yamashita K (9) Tanaka K (10) Yamamoto K (11) Makino T (12) Takahashi T (13) Ueyama A (14) Kurokawa Y (15) Sato E (16) Ohkura N (17) Sakaguchi S (18) Wada H (19) Eguchi H (20) Doki Y

Nature communications

Utilizing scRNA/TCRseq, CITEseq, and a novel assay for cell-bound anti-PD-1 to study the dynamics of T cells targeted by anti-PD-1, Nose and Yasumizu et al. first found that abundance of progenitor-exhausted CD8+ T cells (Tpex) in metastasis-free lymph nodes (LNs), but not tumors or metastatic LNs, correlated with better prognosis in patients with anti-PD-1-naive gastric cancer. Anti-PD-1 promoted the proliferation of anti-PD-1high-bound Tpex in LNs, and clonotypes overlapped with intratumoral anti-PD-1-bound exhausted T cells (Tex), suggesting that anti-PD-1high-bound Tpex migrate to the tumor, where they differentiate into Tex.

Contributed by Ute Burkhardt

ABSTRACT: While progenitor-exhausted T cells (Tpex) expressing TCF1 and PD-1 are crucial for the therapeutic effect of immune checkpoint inhibitors (ICIs) with therapeutic anti-PD-1 antibodies (aPD-1), the dynamics of ICI-bound Tpex are not fully understood. In this study, we investigate ICI-bound T cells in detail using combined sequencing analysis at the single-cell level. By analyzing samples from gastrointestinal cancer patients with or without ICI treatment, we find that Tpex are enriched in proximal lymph nodes (LNs) and proliferate at a high rate after ICI treatment. Importantly, aPD-1 high-bound Tpex in LNs share T-cell receptor clonotypes with intratumoral exhausted CD8(+) T cells (Tex), suggesting their migration to tumor sites after ICI treatment. This study thus provides new insights into how ICIs enhance anti-tumor immunity by acting on Tpex in LNs, deepening our understanding of the cellular mechanisms underlying ICI therapy.

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate Sch

Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (2) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), The University of Osaka, Suita, Japan. (3) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. tsaito@gesurg.med.osaka-u.ac.jp. (4) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (5) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (6) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (7) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (8) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (9) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (10) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (11) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (12) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (13) Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. Pharmaceutical Research Division, Shionogi & Co., Ltd., Toyonaka, Japan. (14) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (15) Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan. (16) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. Department of Basic Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Osaka, Japan. (17) Experimental Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Suita, Japan. (18) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan. (19) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan. (20) Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Osaka, Suita, Japan.

Citation: Nat Commun 2026 Apr 8 Epub04/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41951588

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Immunogenic tumor cell death and T-cell-derived IFN-γ elicit tumoricidal macrophages to potentiate OX40 immunotherapy

Spotlight 

(1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

Cell reports. Medicine

Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

Contributed by Shishir Pant

(1) Liu Y (2) Zhao J (3) Yang K (4) Ma Q (5) Zhang D (6) Xu L (7) Zhang Z (8) Yin Z (9) Chen J (10) Wang Y (11) Wang H (12) Zhou F (13) Han M (14) Wang J (15) Li F (16) Xu Y (17) Yang Y (18) Wang W (19) Huggett S (20) Chung A (21) Gan J (22) Zhang B (23) Zhou Z (24) Cao Y (25) Ding D (26) Wang M (27) Zhang H

Cell reports. Medicine

Using a bilateral, humanized OX40 MC38 tumor model, Liu and Zhao et al. demonstrated that OX40 agonist Ab (agOX40) therapy increased infiltration of NOS2+ pro-inflammatory macrophages and effector CD8+ T cells. T cell-derived IFNγ synergized with DAMP-induced TLR4 signaling to reprogram TAMs toward a pro-inflammatory and tumoricidal NOS2+ state. agOX40-mediated depletion of OX40+Foxp3+ Tregs further potentiated NOS2+ TAM polarization. A combination of MPLA, IFNγ, and agOX40 reprogrammed TAMs, promoted DC maturation, and induced durable tumor regression. ICD-inducing cyclophosphamide enhanced agOX40 therapy.

Contributed by Shishir Pant

ABSTRACT: Understanding the mechanisms limiting OX40 agonist antibody efficacy is critical for developing more effective combination immunotherapies. Tumor microenvironment (TME) analysis revealed that OX40-antibody-responsive mice harbored tumor-associated macrophages (TAMs) with elevated NOS2 expression and heightened pattern recognition receptor (PRR) activation and interferon gamma (IFN-γ) signaling. In addition, patients with more favorable treatment responses to OX40 antibody therapy exhibited increased NOS2 expression. Mechanistically, tumor-infiltrating T-cell-derived IFN-γ synergizes with endogenous ligands of PRR released during immunogenic cell death to drive NOS2+ TAMs reprogramming. Translating these insights into therapeutic strategy, a Combo approach composing of MPLA, IFN-γ, and OX40 agonist antibody is designed to actively polarize TAMs to express NOS2, which mediate tumor clearance through an NOS2-dependent cytotoxicity. Moreover, OX40-antibody-mediated regulatory T cell (Treg) depletion potentiated NOS2+ macrophage induction. This multimodal strategy offers a promising solution to overcome the limitations of OX40 antibody monotherapy and enhance outcomes of the OX40-targeted immunotherapies.

Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Na

Author Info: (1) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China; Henan Academy of Sciences, Zhengzhou 450046, China. (2) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; College of Materials Science and Engineering, Shenzhen University, Shenzhen 518071, China. (3) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (4) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (5) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (6) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (7) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (8) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (9) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (10) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (11) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (12) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (13) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (14) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (15) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (16) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (17) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (18) Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. (19) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (20) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (21) HiFiBiO (Shanghai) Co. Ltd., Cambridge, MA 02139, USA. (22) NovelBio Bio-Pharm Technology Co., Ltd., Shanghai 201114, China. (23) Faculty of Life Science, University College London, London WC1E 6BT, UK. (24) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (25) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China. (26) Henan Provincial People's Hospital & the People's Hospital of Zhengzhou University, Zhengzhou 450003, China. (27) State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and Frontiers Science Center for Cell Responses, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin 300071, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China. Electronic address: hongkai@nankai.edu.cn.

Citation: Cell Rep Med 2026 Mar 26 102699 Epub03/26/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41895288

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Tim-3-targeted vaccines overcome tumor immunosuppression and reduce cDC1 dependence to elicit potent anti-tumor immunity Spotlight 

(1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

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

Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

Contributed by Shishir Pant

(1) Fu C (2) Ma T (3) Clausen BE (4) Mellman I (5) Jiang A

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

Fu et al. showed that an i.v. or s.c. Tim3-targeted vaccine, generated by conjugating antigens to anti-Tim3 antibodies, delivered antigens to both cDC1s and cDC2s and elicited robust and durable CD8+ T cell responses. This Tim3-targeted vaccine restored cross-priming in both β-catenin-driven DC dysfunction and established tumor-mediated immunosuppression across different tumor settings. In Batf3-/- mice lacking cDC1s, CD8+ T cell priming and tumor control were reduced, but not eliminated. A single dose of anti-Tim3 neoantigen vaccine eradicated large established solid tumors and generated memory responses in a CD8+ T cell-dependent manner.

Contributed by Shishir Pant

ABSTRACT: Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-_-catenin(active) mice, which model _-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3(-/-) mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health

Author Info: (1) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824. (2) Department of Computer Science and Engineering, School of Engineering and Computer Science, Oakland University, Rochester, MI 48309. (3) Institute for Molecular Medicine and Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University, Mainz 55131, Germany. (4) Department of Biochemistry and Biophysics, School of Medicine, University of California, San Francisco, CA 94143. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129. (5) Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI 48202. Immunology Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI 48824.

Citation: Proc Natl Acad Sci U S A 2026 Mar 24 123:e2518080123 Epub03/19/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41855265

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Targeting NK cell CLEC12B enhances cancer immunotherapy Spotlight 

(1) Sun P (2) Xu X (3) Hu B (4) Zhang K (5) Khan A (6) Chen H (7) Liu H (8) Khan S (9) Tao Q (10) Nashan B (11) Sun C

Nature immunology

Sun and Xu et al. showed that high expression of the C-type lectin receptor CLEC12B by tumor-infiltrating cells correlated with poor clinical prognosis in patients with HCC. NK cell- specific-Clec12b-/- mice exhibited reduced cancer cell growth and extended survival in HCC, CRC, and metastatic melanoma models. CLEC12B was upregulated on NK cells in the TIME and interacted with lipoprotein lipase to induce CLEC12B–ITIM-mediated inhibitory signaling in NK cells. A nanobody specific for CLEC12B safely revived NK cell activity, suppressed tumor progression, and synergized with anti-PD-1 and chemotherapy in mouse and humanized mouse tumor models.

Contributed by Paula Hochman

(1) Sun P (2) Xu X (3) Hu B (4) Zhang K (5) Khan A (6) Chen H (7) Liu H (8) Khan S (9) Tao Q (10) Nashan B (11) Sun C

Nature immunology

Sun and Xu et al. showed that high expression of the C-type lectin receptor CLEC12B by tumor-infiltrating cells correlated with poor clinical prognosis in patients with HCC. NK cell- specific-Clec12b-/- mice exhibited reduced cancer cell growth and extended survival in HCC, CRC, and metastatic melanoma models. CLEC12B was upregulated on NK cells in the TIME and interacted with lipoprotein lipase to induce CLEC12B–ITIM-mediated inhibitory signaling in NK cells. A nanobody specific for CLEC12B safely revived NK cell activity, suppressed tumor progression, and synergized with anti-PD-1 and chemotherapy in mouse and humanized mouse tumor models.

Contributed by Paula Hochman

ABSTRACT: Natural killer (NK) cells are innate immune effectors, but their cytotoxic potential can be compromised within the immunosuppressive tumor microenvironment. Identifying molecular mechanisms that underly this dysfunction is essential for advances in cancer immunotherapy. Here we show that CLEC12B, a C-type lectin receptor, functions as an inhibitory checkpoint that restricts NK cell-mediated antitumor immunity. High expression of CLEC12B by tumor-infiltrating NK cells correlates with poor clinical prognosis in patients with hepatocellular carcinoma. We identify lipoprotein lipase as a functional ligand for CLEC12B, triggering inhibitory signaling that suppresses NK cell activation. We developed a high-affinity nanobody as a potential therapeutic that disrupts the CLEC12B-lipoprotein lipase axis, thereby revitalizing NK cell activity and suppressing tumor progression in preclinical models. Furthermore, this nanobody has potent synergistic efficacy when combined with PD-1 blockade. These findings establish CLEC12B as a promising therapeutic target for rearming the immune system against solid malignancies.

Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Prov

Author Info: (1) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (2) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (3) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (4) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (5) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (6) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (7) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (8) Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. (9) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. Clinical Research Hospital of Chinese Academy of Sciences, University of Science and Technology of China, Hefei, China. (10) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. Transplant & Immunology Laboratory, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. The Transplantation Center, First Affiliated Hospital, School of Life Sciences and Medical Center, University of Sciences & Technology of China, Hefei, China. Research Centre of Big Data and Artificial Intelligence of Medicine, Hospital of Sun Yat-Sen University, Guangzhou, China. (11) Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn. Institute of Immunology, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. charless@ustc.edu.cn.

Citation: Nat Immunol 2026 Mar 17 Epub03/17/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41844941

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Cancer cell-derived sialylated IgG interacting with Siglec-7/9/10 is a potential immunotherapeutic target in pancreatic cancer Spotlight 

(1) Zhang S (2) Cui M (3) Huang X (4) Feng X (5) Xiao R (6) Liu Q (7) Bai J (8) Han X (9) Liu X (10) Xu W (11) Huang J (12) Liao Q (13) Zhao Y (14) Qiu X

Cell reports. Medicine

Zhang et al. identified sialic acid-bearing IgG (SIA-IgG) in PDAC cells, which correlated positively with immunosuppressive (IS) TAM infiltration, and negatively with survival. SIA-IgG potently induced IS TAMs via sialic acid binding to Siglecs 7/9/10, which upregulated CD206, ARG1, and M2-like cytokines in TAMs. In a positive feedback loop, TAM-derived TGFβ promoted SIA-IgG secretion in cancer cells by enhancing the IgG heavy chain and sialyltransferase ST6GAL1. An anti-SIA-IgG mAb was effective in s.c. and orthotopic PDAC models, including PDX and T cell-deficient tumors, inhibited IS-TAM infiltration, and increased CD8+ T cell infiltration.

Contributed by Morgan Janes

(1) Zhang S (2) Cui M (3) Huang X (4) Feng X (5) Xiao R (6) Liu Q (7) Bai J (8) Han X (9) Liu X (10) Xu W (11) Huang J (12) Liao Q (13) Zhao Y (14) Qiu X

Cell reports. Medicine

Zhang et al. identified sialic acid-bearing IgG (SIA-IgG) in PDAC cells, which correlated positively with immunosuppressive (IS) TAM infiltration, and negatively with survival. SIA-IgG potently induced IS TAMs via sialic acid binding to Siglecs 7/9/10, which upregulated CD206, ARG1, and M2-like cytokines in TAMs. In a positive feedback loop, TAM-derived TGFβ promoted SIA-IgG secretion in cancer cells by enhancing the IgG heavy chain and sialyltransferase ST6GAL1. An anti-SIA-IgG mAb was effective in s.c. and orthotopic PDAC models, including PDX and T cell-deficient tumors, inhibited IS-TAM infiltration, and increased CD8+ T cell infiltration.

Contributed by Morgan Janes

ABSTRACT: The limited effectiveness of T cell-based immune checkpoint blockade (ICB) therapy in most patients with pancreatic ductal adenocarcinoma (PDAC) is largely due to poor CD8(+) T cell infiltration and a highly immunosuppressive microenvironment driven by excessive myeloid cell accumulation. This highlights the urgent need for new immunotherapy targets and strategies. In this study, an identified pro-cancer factor, cancer cell-derived sialylated IgG (SIA-IgG), is found to be significantly overexpressed in pancreatic cancer cells. SIA-IgG inhibits macrophage phagocytosis and induces an M2-like immunosuppressive phenotype through interactions with Siglec-7/9/10. SIA-IgG and TGF-_1, a key immunosuppressive factor, reinforce each other in a positive feedback loop, promoting immune evasion in PDAC. Blocking SIA-IgG with specific monoclonal antibodies shows significant therapeutic potential through reversal of PDAC's immunosuppressive microenvironment. Our findings identify the SIA-IgG/Siglec axis as an immunotherapeutic target for PDAC, offering a feasible approach for the development of immunotherapeutic strategies.

Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 10019

Author Info: (1) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (2) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: cuiming@pumch.cn. (3) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China; Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing 210031, China. (4) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (5) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (6) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (7) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (8) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (9) State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Research Center for Molecular Pathology, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (10) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (11) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. (12) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. (13) Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China. Electronic address: zhao8028@263.net. (14) Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing 100191, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China. Electronic address: qiuxy@bjmu.edu.cn.

Citation: Cell Rep Med 2026 Mar 17 7:102660 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41850238

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Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy Spotlight 

(1) Shi T (2) Wu Y (3) Cai Y (4) Luo Y (5) Ren S (6) Cao Y (7) Tang Y (8) Jiang Z (9) Hu S (10) Xie W (11) Chen Y (12) Shen L (13) Xing H (14) Wei J

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

Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils.

Contributed by Morgan Janes

(1) Shi T (2) Wu Y (3) Cai Y (4) Luo Y (5) Ren S (6) Cao Y (7) Tang Y (8) Jiang Z (9) Hu S (10) Xie W (11) Chen Y (12) Shen L (13) Xing H (14) Wei J

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

Chi et al. engineered a recyclable PD-L1 degrader (RECYC) by fusing a moderate-affinity peptide binder of PD-L1 to an aptamer against the ubiquitous endolysosomal trafficking receptor CI-M6PR. RECYC robustly degraded PD-L1 in tumor and myeloid cells, and exhibited pH-sensitive dissociation from PD-L1, enabling repeated knockdown following membrane recycling. I.v. RECYC outperformed anti-PD-L1 in multiple tumor models. and drove greater PD-L1 knockdown in tumor and myeloid cells, which correlated with efficacy. RECYC enhanced T cell infiltration and early activation, and uniquely promoted M1/N1-like skewing in tumor-associated macrophages and neutrophils.

Contributed by Morgan Janes

ABSTRACT: The efficacy of immune checkpoint blockade is often limited by intrinsic immunosuppressive networks within the tumor immune microenvironment (TIME). Despite progress in cancer treatment, current extracellular targeted protein degradation approaches often overlook the multicellular distribution and crosstalk of immune checkpoints. Here we reported a Receptor-mediated Endolysosomal recYcling Chimera (RECYC) platform. RECYC employs a CI-M6PR-targeting aptamer that remains stable across late endosomal pH and a protein-binding peptide with moderate affinity and pH responsiveness, which together drive recycling and sustained checkpoint clearance. In ex vivo co-culture and in vivo murine models, RECYC efficiently eliminated programmed death-ligand 1 (PD-L1) expression from both tumor cells and tumor-associated myeloid cells (macrophages, neutrophils and dendritic cells). By converting an immunosuppressive TIME to an immunostimulatory state, RECYC remodeled the tumor-immune network in an anti-tumor direction, thereby enhancing CD8(+) T cell response and repolarizing immunosuppressive myeloid cells. Moreover, in both immune-cold and immune-hot murine cancer models, RECYC demonstrated superior anti-tumor effect compared to PD-L1 blockade treatment. Collectively, we propose an effective strategy to induce recycling and broad checkpoint clearance in the TIME, which in turn reprograms the multicellular tumor-immune network to achieve durable immunotherapy responses.

Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nan

Author Info: (1) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (2) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (3) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (4) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (5) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (6) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (7) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (8) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (9) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. (10) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (11) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (12) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (13) Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo and Biosensing, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. (14) Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China. ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing 210061, China. Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China.

Citation: Proc Natl Acad Sci U S A 2026 Mar 10 123:e2525047123 Epub03/02/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41770936

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