A team led by Li Lei, Ma Jian, and Gao Yang from the First Affiliated Hospital of Xi'an Jiaotong University has addressed challenges in Immune checkpoint blockade (ICB) therapy in their paper Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage, published in the oncology journal Cancer Cell.

ICB therapy has revolutionized treatment for various cancers, yet its success remains stalled in immune-cold tumors like prostate cancer, where clinical response rates hover below 5 percent.

While radiotherapy theoretically boosts anti-tumor immunity by inducing DNA damage and activating the cGAS–STING pathway, multiple clinical trials have shown disappointing results for radiotherapy-immunotherapy combinations in prostate cancer, leading to a therapeutic deadlock.

The team's research uncovers the internal regulatory mechanisms that tumor cells use to suppress radiotherapy-induced immune activation, providing a vital explanation for treatment resistance and proposing a new path forward.

By analyzing multi-cohort clinical data, the researchers found that some prostate and endometrial cancer patients exhibit low immune cell infiltration despite a high tumor mutational burden (TMB). This suggests that traditional biomarkers alone are insufficient to predict the success of immunotherapy.

The study identifies USP7 as a key regulatory molecule that, when targeted, could unlock the radiotherapy-induced immune response, offering a way to overcome resistance and optimize combination therapies.

This research provides a theoretical and practical foundation for personalizing radiotherapy-immunotherapy, which is crucial for improving outcomes in patients with typically non-responsive tumors.