In conclusion, our results provide a rational combination therapeutic strategy by targeting PRMT5 in R/R MCL patients featured with frequent mutations in ATM, TP53, and CDKN2A. Considering the synergistic effect of the inhibition of both PRMT5 and DDR or cell cycle effector molecules, we anticipate our preclinical study has the translational potential to lead to new clinical trials for MCL. This evidence concerns the gene TP53 and mantle cell lymphoma.