Data from DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8<sup>+</sup> T-cell Immunity in Hepatocellular Carcinoma

<div>Abstract<p>Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8⁺ T cells to impair antitumor immunity and thereby promote HCC progression. TGFβ1 induced NET formation, which recruited CD8⁺ T cells. Binding to NET-DNA inhibited CD8⁺ T cells function while increasing apoptosis and TGFβ1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not <i>TMCO6</i>^−/− mice. In clinical samples, CD8⁺ T cells expressing TMCO6 had an exhausted phenotype. TGFβ1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression <i>in vivo</i>. Collectively, this study unveils the role of NET-DNA in impairing CD8⁺ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression.</p>Significance:<p>TMCO6 is a receptor for DNA of NETs that mediates CD8⁺ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.</p></div>