Search
Search articles by title, abstract,author or doi
Advanced search

CD93 at the vascular–immune nexus

Yujie Guo , Lieping Chen , Yuwen Zhu

Vita ››

PDF (1247KB)
Vita > Cutting Edge > DOI: 10.15302/vita.2026.08.0068
Vita Open AccessPublished:

CD93 at the vascular–immune nexus

Author information +
History +
Vita () Cite this article
PDF (1247KB)

The CD93 pathway has been involved in tumor vascular dysfunction, which limits T cell infiltration into solid cancers. In this issue of Vita, Yu et al. uncover a distinct role for myeloid CD93 as an immune suppressor that restrains antitumor T cell responses during T cell engager (TCE) therapy, potentially through CD69, highlighting a resistance mechanism to TCE therapy in B-NHL.

登录浏览全文

4963

注册一个新账户 忘记密码

T cell engager (TCE) therapy, which redirects T cells to kill tumor cells, has made remarkable progress in cancer therapy over the past decade1. However, like other T cell-based immunotherapies, TCE therapy fails to generate durable responses in many patients because of immune escape and resistance mechanisms within the tumor microenvironment (TME). Resistance to TCE therapy has primarily been attributed to tumor-intrinsic and T cell-related mechanisms, including loss of the target antigen and insufficient T cell infiltration. In contrast, how other immune and stromal components of the TME shape responses to TCE therapy remains poorly explored.
In this issue, Yu et al.2 reported tumor-infiltrating myeloid cells (TIMCs) as an important mediator of TCE resistance in B‑cell Non‑Hodgkin Lymphoma (B-NHL). The authors found that CD163+ myeloid cells, presumably the dominant immunosuppressive myeloid cell type, are actively recruited into the tumors in response to TCE therapy. Depletion or modulation by BTK inhibition of these TIMCs restores TCE-triggered antitumor T-cell response in B-NHL, supporting that TIMC recruitment contributes to the resistance to TCE therapy. Comparative analysis of datasets under BTK inhibition indicated that CD93 was a robust target under the regulation of BTK signaling. CD93 ablation in the myeloid compartment completely abrogated the effect of a BTK inhibitor in promoting TCE therapy in a mouse model, establishing that CD93 is the downstream target of BTK signaling to suppress the antitumor effect induced by TCE therapy.
CD93 is a type I transmembrane protein of the C-type lectin-like domain (CTLD) superfamily, with an extracellular region comprising a CTLD, a Sushi-like domain, and five EGF-like repeats. It is primarily expressed by myeloid cells, immature B cells, and endothelial cells, where it regulates inflammation and angiogenesis. The known ligands for CD93 include at least extracellular matrix proteins multimerin-2 (MMRN2), insulin-like growth factor-binding protein 7 (IGFBP7), and IL-17D3.
The CD93 pathway is enriched in the TME, where CD93 is predominantly expressed by tumor vasculature and macrophages3. MMRN2 is primarily upregulated in tumor vasculature, whereas IGFBP7 is more broadly produced by stromal cells4. In solid tumors, CD93 blockade normalizes tumor vasculature, thereby promoting tumor perfusion, reducing hypoxia, and enhancing immune cell infiltration5. Rather than pruning tumor vessels, CD93 blockade promotes the maturation and function of existing vasculature, creating a favorable TME for cancer therapy6. Accordingly, CD93 blockade enhances responses to immune checkpoint blockade and adoptive cell therapy5,7, supporting the clinical development of CD93-targeted therapies in solid tumors (NCT05785754).
Here, the study by Yu et al.2 revealed a direct suppressive effect of myeloid CD93 on T cells, which echoes a previous report that CD93 on myeloid cells limits antitumor T cell infiltration and function8. Furthermore, the authors identified CD69 as the receptor on T cells for CD93 engagement. The direct interaction between CD93 and CD69 was verified by SPR, with both CTLD and the EGF-like domains of CD93 capable of binding CD69. CD69 engagement by CD93 triggered a suppressive signal, proximal to TCR signaling. Blockade of the CD93−CD69 interaction with a CD93 monoclonal antibody enhanced T cell response and promoted TCE therapy. Together, the study identifies myeloid CD93 as a potential immunosuppressive factor during TCE therapy and suggests a role for CD93 in directly modulating T cell responses.
Several outstanding questions remain regarding the CD93-CD69 axis. First, the nature of CD69-mediated suppression on T cells remains to be explored. CD69 is rapidly induced upon T cell activation, and its expression is traditionally considered an early sign of T cell activation. CD69 is best known for its cis interaction with sphingosine-1-phosphate receptor 1 (S1PR1), which antagonizes S1P signaling and regulates T cell egress from lymphoid tissues9. The current study reveals a new role for CD69, whereby engagement by CD93 suppresses signaling proximal to the TCR. However, the intracellular domain of CD69 lacks an ITIM or ITIM-like motif which classical inhibitory receptors utilize to recruit tyrosine phosphatases. Defining how CD69 counteracts TCR signaling, including whether it involves additional signaling partners, requires further investigation. Second, the crosstalk between the vascular and T cell-suppressive functions of CD93 in the TME remains to be delineated. For example, MMRN2 and IGFBP7 may modulate the CD93−CD69 interaction, while it is unclear whether CD93 engagement alters the association between CD69 and S1PR1. Given the critical role of T cell–endothelial cell interactions in T cell extravasation and tumor infiltration10, it will be important to determine whether the CD93-CD69 axis directly regulates this process. Finally, whether CD69 engages CD93 to shape myeloid cell differentiation or regulate vascular function warrants further investigation.
CD93 may dampen antitumor immunity by both vascular dysfunction that limits effector immune cell infiltration and direct inhibition of T cell function via CD69 (Fig. 1). The identification of CD69 as an inhibitory receptor for CD93 expands the role of CD93 in sustaining an immunosuppressive TME and beyond. This finding may have important implications for further improvement of TCE therapy and shed light on future immunotherapy targeting this ever-complicated pathway.

[1]

Baeuerle, P.A., Sauer, K., Grieshaber-Bouyer, R. & Michaelson, J.S. J. Exp. Med. 223, e20251652 (2026).

[2]

Yu, H. et al. Vita https://doi.org/10.15302/vita.2026.08.0064 (2026).

[3]

de Alves Pereira, B., Barbera, S., Lugano, R. & Dimberg, A. Br. J. Pharmacol. https://doi.org/10.1111/bph.70577 (2026).

[4]

Li, Y. et al. Cancer Cell Int. 23, 189 (2023).

[5]

Sun, Y. et al. Sci. Transl. Med. 13, eabc8922 (2021).

[6]

Sun, Y. et al. Mol. Ther. 33, 5017–5027 (2025).

[7]

Sun, Y. et al. J. Immunother. Cancer 13, e010554 (2025).

[8]

Jiang, D. et al. J. Immunother. Cancer 12, e010148 (2024).

[9]

Cibrián, D. & Sánchez-Madrid, F. Eur. J. Immunol. 47, 946–953 (2017).

[10]

Alcaide, P. Cold Spring Harb. Perspect. Med. 12, a041170 (2022).

RIGHTS & PERMISSIONS

The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Cite this article

Download citation ▾
Guo, Y., Chen, L., Zhu, Y.  CD93 at the vascular–immune nexus  Vita https://doi.org/10.15302/vita.2026.08.0068 ()
AI Summary AI Mindmap
PDF (1247KB)
Sections
Figures
References

233

Accesses

0

Citation

Detail

Recommended

AI思维导图

/

〈 〉