FAM135B Deficiency Inhibits Cytotoxic T-Cell Activity in Triple-negative Breast Cancer by Blocking the IFI16-dependent STING Pathway

Abstract Despite advances in immune checkpoint blockade (ICB) for cancer treatment, only a minority of triple-negative breast cancer (TNBC) patients derive benefits, and the underlying mechanisms remain largely unknown. Herein, sequence similarity 135 family member B (FAM135B) is identified as a regulator of antitumor immunity in TNBC. Single-cell sequencing data and functional assays demonstrate the critical role of FAM135B in activating cytotoxic T cells and improving the efficacy of ICB treatment by stimulating the STING pathway. Specifically, FAM135B interacts with IFI16, inhibiting its ubiquitination and proteasomal degradation by competitively blocking its binding to the E3 ligase TRIM21, thereby initiating the IFI16-dependent STING signaling, ultimately leading to increased cytotoxic T cell activity. The deubiquitination of IFI16 at lysine 143 and lysine 561 is 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 TNBC patients.