{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T11:21:16Z","timestamp":1784373676187,"version":"3.55.0"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"44","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,10,31]]},"abstract":"<jats:p>\n                    RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    is a hotspot mutation associated with poor prognosis in several cancers. By gene editing, we generated endogenous homozygous and heterozygous RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    mutations, which result in up-regulated RAC1 activity and mammalian target of rapamycin (mTOR) signaling. RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    tumors grow faster than RAC1\n                    <jats:sup>WT<\/jats:sup>\n                    tumors in immune-proficient mice and are resistant to anti\u2013programmed death protein 1 (PD1). Flow cytometry and scRNA-seq analyses reveal that RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    cells form \u201ccold\u201d tumors with an immunosuppressive microenvironment and reduced tumor-immune cell interactions. Mechanistically, RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    up-regulates glycosphingolipid biosynthesis to activate mTORC1 signaling in tumor cells, which in turn increases glycolysis, impairs key chemokine production, and decreases IFNGR1 expression of the tumor cells. mTORC1 inhibition by rapamycin resensitizes the RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    tumors to anti-PD1 treatment by reversing effects of RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    mutation. These results demonstrate a mechanism of RAC1\n                    <jats:sup>A159V<\/jats:sup>\n                    -driven immune evasion and suggest an approach of combining the targeting of RAC1-mTOR signaling with immune checkpoint inhibitor for the treatment of a type of immune-cold tumors.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea1212","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T17:58:36Z","timestamp":1761760716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Tumor-derived RAC1\n                    <sup>A159V<\/sup>\n                    mutation promotes an immunosuppressive microenvironment that represses response to immune checkpoint 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