Despite great success in certain cancers, immunotherapy made little progress in treating immune “cold” tumors, like prostate cancer, largely attributed to an immunesuppressive tumor microenvironment with elusive mechanisms. Here, we report in prostate cancer cells a positive feed-back loop driven by PSAT1 that could be targeted to render effective cytotherapy by NK cells. In the loop, PSAT1 increases YBX1 phosphorylation by MARK2, promoting its nuclear translocation to upregulate PSAT1 transcription. Meanwhile, YBX1 also promotes HLA-E transcription, a ligand for inhibitory KIRs inactivating NK cells. As a result, the PSAT1 loop serves as a buff to sustain YBX1 and HLA-E expression, suppressing NK killing of prostate cancer cells.