By using an ex vivo synthetic small interfering (si)RNA approach to inhibit “casitas B-lineage lymphoma proto-oncogene b (cblb)”, a member of the mammalian family of RING E3 ubiquitin ligases, we demonstrated this as a potentially rational approach to achieve such goals, as it profoundly improves the efficacy of ACT for cancer immunotherapy. The gene discussed is CBLB; the disease is cancer.