Abstract Immune checkpoint therapy shows impressive and durable clinical responses in cancer patients, but the genetic determinants that enable cancer cells to respond to anti-PD-1 therapy are still elusive. Herein, we identified that NIPBL deficiency promotes endogenous retrovirus (ERV) expression in tumour cells, which in turn inactivates CD8+ tumour-infiltrating lymphocytes (TILs) via the PD-L1/PD-1 inhibitory checkpoint pathway. Mechanistically, NIPBL deficiency impairs DNMT1 transcription, preventing DNMT1 from suppressing ERV expression in tumour cells; ERVs stimulate PD-L1 expression by inducing the STAT2-IRF9 complex, a downstream event of double-stranded RNA (dsRNA)-MAVS-IRF3 signalling, and thereby suppress CD8 TIL-mediated immunity. An anti-PD-1 monoclonal antibody achieved remarkable therapeutic effects in Nipbl -deficient syngeneic tumour models and improved host survival by eliciting an antitumour memory immune response. Cancer patients harbouring mutations of cohesin subunits and regulators plus DNMT1 had significantly better responses to anti-PD-1 therapy than their non-mutated counterparts did. Our study reveals a novel mechanism by which cohesin complex deregulation stimulates ERV expression by impairing DNMT1 expression and fosters an immunosuppressive tumour microenvironment by activating the PD-L1/PD-1 inhibitory checkpoint.

Cohesin mutation sensitizes cancer cells to anti-PD-1 therapy through endogenous retrovirus-mediated PD-L1 upregulation