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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,12,30]]},"abstract":"<jats:p>Despite great success in certain cancers, immunotherapy made little progress in treating immune cold tumors, largely attributed to an immune-suppressive tumor microenvironment with elusive mechanisms. Here, we report in prostate cancer cells a positive feedback loop driven by phosphoserine aminotransferase 1 (PSAT1) that could be targeted to render effective cytotherapy by natural killer (NK) cells. In the loop, PSAT1 increases Y-box binding protein 1 (YBX1) phosphorylation by microtubule affinity-regulating kinase 2, promoting its nuclear translocation to upregulate PSAT1 transcription. Meanwhile, YBX1 also promotes human leukocyte antigens E (HLA-E) transcription to inactivate NK cells. Consequently, the PSAT1 loop serves as a buff sustaining YBX1\/HLA-E expression, suppressing NK killing of prostate cancer cells. Targeting loop molecules, such as PAST1, effectively potentiates tumor suppression by NK cells both in-vitro and in-vivo. Thus, our study uncovered a heretofore unrecognized nonautonomous mechanism for PSAT1, as well as a molecular buff for YBX1, to drive tumor growth by evading NK immunity, providing a promising target for NK cytotherapy of immune cold tumors.<\/jats:p>","DOI":"10.1073\/pnas.2505658122","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T20:00:56Z","timestamp":1766433656000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["A PSAT1 buff of YBX1 transcriptionally sustains HLA-E-mediated evasion of NK immunity"],"prefix":"10.1073","volume":"122","author":[{"given":"Yangyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Oncology, Beijing Shijitan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science","place":["Beijing, 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