Reinvigorating COTL1high NK cells via GITR signalling overcomes immune checkpoint blockade resistance in tsMHC-I-impaired tumours.

Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-Iimpaired) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-Iimpaired remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1high natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1+ macrophages coexpress GITRL and engage GITR on COTL1high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic-H3K27ac-RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-Iimpaired models. Our findings identify COTL1high NK cells as key determinants of ICB responsiveness and highlight the GITRL-GITR axis as a promising therapeutic target for tsMHC-Iimpaired tumours.