IGSF3 binds to TNFR2 on Treg to facilitate immunosuppression in cervical cancer.

The clinical success of immune checkpoint blockades has revolutionized oncology; however, their efficacy in cervical cancer remains limited, primarily due to intricate tumor immune evasion mechanisms. Here, we identify elevated IGSF3 expression on tumor cells as a key driver enhancing regulatory T cell (Treg) infiltration and function. Crucially, we reveal a previously unrecognized ligand-receptor pair: IGSF3 on cervical cancer cells binds to TNFR2 on Tregs, activating NF-κB pathway and thereby amplifying Treg-mediated immunosuppression. Through structure-based virtual screening and rigorous multi-level validation, we developed purpurogallin, a conventionally recognized antioxidant compound, as a novel IGSF3 inhibitor, which effectively disrupts the IGSF3-TNFR2 interaction, reduces Treg abundance, suppresses tumor growth, and synergizes with anti-PD-1/anti-CTLA-4 antibodies. Notably, pretreatment with purpurogallin followed by PD-1 blockade yields superior therapeutic efficacy compared to concurrent combination therapy. This study establishes IGSF3 as a pivotal regulator of the immunosuppressive microenvironment and unveils a promising sequential immunotherapy strategy for cervical cancer.

• Publication year

  2026

• Venue

  Cancer Letters

• Publication date

  2026-02-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.canlet.2026.218307PMID 41690453
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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