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

Qiaoshi Lian1, Jia Nie2, Jatinder Singh3

  • 1Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Science (New York, N.Y.)
|June 18, 2026
PubMed

Insights

New cancer immunotherapy targets tumor stroma via CD4+ T cells. These cells induce myeloid clusters and TNF, damaging tumor blood vessels and inhibiting growth without directly killing cancer cells.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Biology

Background:

  • Current cancer immunotherapies primarily focus on direct tumor cell killing by immune cells like T lymphocytes.
  • Limitations in existing strategies necessitate the development of alternative therapeutic approaches.

Purpose of the Study:

  • To identify and characterize novel tumor stroma-targeting mechanisms for cancer immunotherapy.
  • To investigate the role of CD4+ T cells in mediating anti-tumor effects through vascular damage.

Main Methods:

  • Utilized multiplex immunofluorescence and single-cell/tissue transcriptomics.
  • Analyzed the interaction between CD4+ T cells, myeloid cells, and tumor vasculature.

Main Results:

  • Discovered that tumor antigen-specific CD4+ T cells can inhibit tumor growth by inducing perivascular myeloid cell clusters.
  • Demonstrated that these clusters contain classically activated macrophages producing TNF, triggered by T cell-derived interleukin-3.
  • Showed that TNF leads to intratumoral endothelial damage and disrupted blood supply, causing localized tumor cell death.

Conclusions:

  • Intratumoral T cell activation can mediate anti-tumor effects by targeting tumor stroma and vasculature.
  • This mechanism bypasses direct tumor cell recognition, potentially overcoming common immune evasion strategies.

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