Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer

Chien-Huan Weng^{1

2

3}, Anais Assouvie^{1

2

3}, Lauren Dong^{1

2

3}, Jean-Christophe Beltra^{3

4}, Sadna Budhu^{1

2

3}, Levi Mangarin^{1

2

3}, Yacine Marouf^{1

2

3}, Lucia Morgado-Palacin^{1

2

3}, Cailian Liu^{1

2

3}, Sébastien Monette⁵, Jonathan F Khan^{1

2

3}, Isabell Schulze^{1

2

3}, Dmitriy Zamarin^{6

7}, Linda Hamadene^{1

2

3}, Fadi Samaan⁶, Daniel Hirschhorn^{1

2

3}, Stephane Pourpe⁶, David Schröder⁶, Roberta Zappasodi^{2

3

8

9}, Pamela M Holland^{10

11}, Niroshana Anandasabapathy^{2

3

12

13}, E John Wherry^{3

14

15}, Jedd D Wolchok^{16

17

18

19

20}, Taha Merghoub^{21

22

23}

Affiliations

¹ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA.
⁶ Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Medicine at Weill Cornell Medicine, New York, NY, USA.
⁹ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA.
¹⁰ Surface Oncology Inc., Cambridge, MA, USA.
¹¹ InduPro, Seattle, WA, USA.
¹² Department of Dermatology, Weill Cornell Medicine, New York, NY, USA.
¹³ Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
¹⁴ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
¹⁷ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
¹⁸ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. jwolchok@med.cornell.edu.
¹⁹ Department of Medicine at Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
²⁰ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA. jwolchok@med.cornell.edu.
²¹ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
²² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
²³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. tmerghoub@med.cornell.edu.

PMID: 41249483
DOI: 10.1038/s41590-025-02321-5

Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer

Chien-Huan Weng et al. Nat Immunol. 2025.

. 2025 Nov 17.

doi: 10.1038/s41590-025-02321-5. Online ahead of print.

Authors

Affiliations

¹ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁴ Department of Biomedicine, University of Basel, Basel, Switzerland.
⁵ Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, The Rockefeller University, Weill Cornell Medicine, New York, NY, USA.
⁶ Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
⁷ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Department of Medicine at Weill Cornell Medicine, New York, NY, USA.
⁹ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA.
¹⁰ Surface Oncology Inc., Cambridge, MA, USA.
¹¹ InduPro, Seattle, WA, USA.
¹² Department of Dermatology, Weill Cornell Medicine, New York, NY, USA.
¹³ Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
¹⁴ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Institute for Immunology and Immune Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
¹⁷ Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
¹⁸ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. jwolchok@med.cornell.edu.
¹⁹ Department of Medicine at Weill Cornell Medicine, New York, NY, USA. jwolchok@med.cornell.edu.
²⁰ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School, New York, NY, USA. jwolchok@med.cornell.edu.
²¹ Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
²² Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. tmerghoub@med.cornell.edu.
²³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. tmerghoub@med.cornell.edu.

PMID: 41249483
DOI: 10.1038/s41590-025-02321-5

Abstract

T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8⁺ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin-NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1-CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1-CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.

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Conflict of interest statement

Competing interests: C.-H.W., A.A., L.D., L.M.-P., L.M., Y.M., C.L., S.M., J.F.K., I.S., D.Z., L.H., F.S., S.P. and D.S. declare no competing interests related to this work. S.B. received royalties from Agenus for work on LAG-3 and TIM-3. D.H. is an inventor on patent applications related to work on OX40 and GITR. R.Z. is an inventor on patent applications related to work on GITR, PD-1 and CTLA4. R.Z. is consultant for Leap Therapeutics, Daiichi Sankyo and IFLI, serves as an SAB member for iTeos Therapeutics and receives grant support from Bristol Myers Squibb and Astrazeneca. P.M.H. was employed by Surface Oncology and is currently employed by InduPro. E.J.W. is a member of the Parker Institute for Cancer Immunotherapy. E.J.W. is an advisor for Absci, Arpelos Biosciences, Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio and Synthekine. E.J.W. is a founder of Arpelos Biosciences, Arsenal Biosciences and Danger Bio, and holds stock in Coherus. N.A. is a consultant for Shennon Biosciences, Panther Life Science, Verrica, Janssen, Immunitas, 23&me, Cellino, Kumquat and Genmab, and serves as an SAB member for Network Bio. J.D.W is a consultant for Ankyra Therapeutics, Apricity, Arsenal Biosciences, Ascentage Pharma, Bicara Therapeutics, Bristol Myers Squibb, Daiichi Sankyo, Imvaq, Takeda, Tizona, Trishula Therapeutics, Immunocore (Data Safety Board) and Scancell. J.D.W. received grant/research support from Bristol Myers Squibb. J.D.W. has equity in Apricity, Arsenal IO/CellCarta, Ascentage, Imvaq, Linneaus, Georgiamune, Maverick/Takeda, Tizona Therapeutics and Xenimmune. J.D.W. is an inventor on the following patents: Xenogeneic DNA vaccines, Newcastle disease viruses for cancer therapy, Myeloid-derived suppressor cell (MDSC) assay, Prediction of responsiveness to treatment with immunomodulatory therapeutics and method of monitoring abscopal effects during such treatment, Anti-PD-1 antibody, Anti-CTLA4 antibodies, Anti-GITR antibodies and methods of use thereof. T.M. acted in the capacity of consultant for Immunos Therapeutics, Daiichi Sankyo Co, TigaTx, Normunity and Pfizer. T.M. is a cofounder of and equity holder in IMVAQ Therapeutics. T.M. has received research support from Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, Aprea Therapeutics, Enterome SA and Realta Life Sciences, and currently receives research funding from Bristol Myers Squibb. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus–based vaccine, neoantigen modeling, immunomodulatory nanoparticles, bi-specific activators, FLT3L, CD40, IL-10, IL10R, GITR, OX40, PD-1, CTLA4 and chimeric receptors targeting melanoma differentiation antigens, B7-H3 and MUC-16, and listed as an inventor on a US Provisional Patent Application (Ser. No. 63/888,188) related to work on CD47 and TSP-1.

References

1. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015). - PubMed - PMC - DOI
1. Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018). - PubMed - PMC - DOI
1. Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019). - PubMed - DOI
1. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8⁺ T cell exhaustion. Nature 571, 211–218 (2019). - PubMed - PMC - DOI
1. Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019). - PubMed - PMC - DOI

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Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer

Affiliations

Thrombospondin-1-CD47 signaling contributes to the development of T cell exhaustion in cancer

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous