This research explores how prostate cancer cells avoid detection by the immune system through the manipulation of the cGAS-STING pathway. Scientists found that SPOP mutations prevent the buildup of DNA in the cell’s cytoplasm, which normally triggers an immune response after radiation damage. Specifically, SPOP usually tags the enzyme TREX1 for destruction, but when mutated, TREX1 levels rise and rapidly clear out the DNA that would otherwise alert the immune system. The study also identifies USP7 as a deubiquitinase that protects TREX1 from being degraded, further aiding tumor evasion. To counter this, the authors demonstrate that inhibiting USP7 restores DNA levels and significantly improves the effectiveness of immunotherapy. These findings suggest that targeting the USP7-SPOP-TREX1 axis could be a vital strategy for making resistant tumors more responsive to combined radiotherapy and immune checkpoint blockade.

References:

• Li L, Ye Q, Ma J, et al. Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage[J]. Cancer Cell, 2026.