TRIM11 potentiates antitumor immunity via inhibition of the IFN-γ/PD-L1 axis.

PD-L1 serves as the ligand for the immune inhibitory checkpoint protein PD-1, and its expression in tumors can be induced by interferon-γ (IFN-γ), leading to immune evasion. While JAK/STAT signaling is known to mediate IFN-γ-induced PD-L1 expression, the mechanisms governing the negative regulation of PD-L1 in response to IFN-γ remain largely unclear. Here, we find that the E3 ubiquitin ligase TRIM11 is significantly stabilized to block the induction of PD-L1 upon treatment with IFN-γ. TRIM11 functions as a tumor suppressor by enhancing cytotoxic T lymphocyte (CTL) activity and potentiating antitumor immunity within the local tumor microenvironment. Mechanistically, TRIM11 and JAK1 interact and mutually regulate each other through post-translational modifications in response to IFN-γ stimulation. JAK1 phosphorylates TRIM11, leading to its stabilization and activation by reducing K48-linked polyubiquitination and subsequent proteasomal degradation. Meanwhile, TRIM11 inhibits JAK1 through K63-linked polyubiquitination, thereby suppressing downstream JAK/STAT signaling, particularly reducing PD-L1 expression. This enhances CTL activity and bolsters antitumor effects in the presence of IFN-γ. Moreover, low expression of TRIM11, IFN-γ, and CD8(+) T cells correlates with poor prognosis in patients, while TRIM11 expression levels could predict sensitivity to immune checkpoint blockade therapy. These findings define a role for the TRIM11/JAK1 axis in IFN-γ-induced PD-L1 expression, suggesting its potential as a therapeutic target to enhance cancer immunotherapy.