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. • IGSF3 highly expressed on cancer cells promotes immunosuppression of Treg. • IGSF3 interacts with TNFR2 on Tregs thus activating NF-κB pathway. • Purpurogallin interrupts IGSF3-TNFR2 axis. • Purpurogallin enhances tumor control and sensitizes tumor to ICBs. • Purpurogallin can serve as a pretreatment to leverage anti-PD1 efficacy.