Core Viewpoint - The emergence and application of immunotherapy have changed the treatment landscape for various malignancies, but its efficacy is limited to a small percentage of patients, particularly in prostate cancer where less than 5% of patients benefit from immune checkpoint inhibitors (ICB) [3][4]. Group 1: Mechanism Insights - Radiotherapy induces DNA damage, potentially leading to immunogenic cell death and the release of cytosolic DNA, which activates the cGAS-STING pathway and initiates type I interferon signaling [3]. - The inherent cGAS-STING activity within cancer cells controls tumor immunogenicity and modulates the effectiveness of ICB therapy, suggesting that reactivating this pathway could overcome resistance to ICB [3][5]. - The study published by a team from Xi'an Jiaotong University highlights that ubiquitination-directed cytosolic DNA degradation governs the immune response to DNA damage, explaining the limited efficacy of DNA damage-based therapies in combination with immunotherapy [4][5]. Group 2: Role of TREX1 and USP7 - The presence of TREX1, a nucleic acid exonuclease, in the cytoplasm rapidly degrades cytosolic DNA fragments, preventing the activation of immune responses [7]. - The study identifies USP7 as a deubiquitinating enzyme that stabilizes TREX1, while SPOP acts as an E3 ubiquitin ligase that promotes TREX1 degradation, thus influencing the accumulation of cytosolic DNA and the activation of the cGAS-STING pathway [8][9]. - In many cancers, mutations in the SPOP gene or overexpression of USP7 lead to elevated levels of TREX1, hindering the effective accumulation of cytosolic DNA and resulting in poor immunotherapy outcomes [8][9]. Group 3: Clinical Implications - Data analysis from cancer patients undergoing radiotherapy and chemotherapy indicates that those with high USP7 expression have fewer tumor-infiltrating lymphocytes and faster disease progression [9]. - The use of USP7 inhibitors can effectively lower TREX1 levels, restoring the activation of the cGAS-STING pathway and enhancing anti-tumor immune responses when used after radiotherapy [9][11]. - The research underscores the potential of targeting USP7 to enhance existing cancer treatment efficacy and suggests that levels of USP7 or TREX1 could serve as biomarkers for predicting the effectiveness of combined radiotherapy and immunotherapy [9][11].