FAM135B Deficiency Inhibits Cytotoxic T-cell Activity in Triple-Negative Breast Cancer by Blocking the IFI16-Dependent STING Pathway

Immune checkpoint blockade (ICB) has improved outcomes for patients with several types of cancer. However, only a minority of patients with triple-negative breast cancer (TNBC) derive benefits, and the underlying mechanisms remain largely unknown. In this study, we identified family with sequence similarity 135 member B (FAM135B) as a regulator of antitumor immunity in TNBC. Single-cell sequencing data and functional assays demonstrated the critical role of FAM135B in activating cytotoxic T cells and improving the efficacy of ICB treatment by stimulating the STING pathway. Specifically, we found that FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking its binding to the E3 ligase TRIM21. This initiated IFI16-dependent STING signaling, which ultimately led to increased cytotoxic T-cell activity. Deubiquitination of IFI16 at lysine 143 and lysine 561 was crucial for FAM135B-mediated activation of the STING pathway. These findings reveal that FAM135B regulates the IFI16-dependent STING pathway and subsequent immune activation. FAM135B may represent a potential predictor of ICB therapeutic responses for patients with TNBC.