CD4⁺ T cells impair tumor growth through IL-3 and TNF-dependent vascular damage.

Authors

Qiaoshi Lian, Jia Nie, Jatinder Singh, Qiang Chen, Jennifer Matta, Waipan Chan, Mariah Balmaceno-Criss, Melanie S Vacchio, Weiming Yu, Alexander D Clark, Elijah Edmondson, Michael C Kelly, Ronald N Germain, Rémy Bosselut

Published in

Science (New York, N.Y.). Volume 392. Issue 6804. Pages eads7910. Jun 18, 2026. Epub Jun 18, 2026.

Abstract

Most cancer immunotherapy strategies are focused on direct tumor killing by immune cells, especially T lymphocytes. Clinical and conceptual limitations of these approaches create a need for additional strategies. We identified a tumor stroma-targeting mechanism in which tumor antigen-specific CD4⁺ T cells inhibit tumor growth through myeloid cell and tumor necrosis factor (TNF)-dependent vascular damage. Multiplex immunofluorescence and single-cell and tissue transcriptomics showed that CD4⁺ T cells trigger the formation of perivascular myeloid cell clusters containing "classically activated" macrophages that produce TNF in response to T cell-derived interleukin-3. TNF causes intratumoral endothelial damage and blood supply disruption, which are associated with localized tumor cell death. Thus, intratumoral antigen-triggered T cell activation can mediate antitumor effects without direct recognition of living tumor cells, thereby avoiding many of the inhibitory mechanisms that limit anti-tumor immunity.

PMID:
42313973
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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