Male infertility affects about 7% of men, but its genetic causes are diverse and mostly unknown. We studied the genomes of 2054 infertile Chinese men to see how genetic factors impact fertility treatment outcomes. We found clear genetic causes in 11.4% of the men, including 13 genes never documented in human infertility before. While overall success rates for fertility treatments were similar across different groups, men with defects in 10 specific genes had very low pregnancy rates, and men with defects in 5 of those genes had no live births at all. We also discovered 41 candidate genes that may cause infertility. Ultimately, this study shows that genetic testing serves a powerful tool to potentially help, guide and improve fertility treatments.

PD-L1 is best known as the molecular "off switch" cancer cells use to disable the immune system at their surface. In recent years, however, it has become clear that PD-L1 can also enter the nucleus, yet what drives it there, and what it does once inside, has remained largely a mystery. Researchers from Zhejiang University and the University of Macau now provide an answer: DDB1, a protein adaptor, tags PD-L1 with K63-linked ubiquitin chains at the K185 site—a modification that does two things at once. It removes an acetylation mark that would otherwise keep PD-L1 out of the nucleus, and it enables the nuclear protein to bind DNA and switch on a program of immunosuppressive genes. In breast cancer patients resistant to immunotherapy, this nuclear form of PD-L1 was markedly elevated. Remarkably, thalidomide, an old drug already used for multiple myeloma, disrupts the DDB1–PD-L1 partnership. Combined with anti-PD-1 antibody in mouse models, the therapy shrank tumors dramatically, boosted infiltration of cancer-killing T cells, and extended survival. Published in Science Bulletin, the study uncovers a non-canonical route to immune evasion and offers a "repurposed" combination strategy poised for clinical testing.