Genetic deletion of Spata2 and CYLD enhances infiltration of anti-tumoral CXCR3 T/NK cells and anti-PD-1-mediated tumor regression in vivo. Our results raise the intriguing possibility of therapeutically targeting the SPATA2-CYLD axis to improve responses of colorectal cancer to PD-(L)1 blockade and other immunotherapies. The gene discussed is SPATA2; the disease is colorectal cancer.