{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:58:46Z","timestamp":1785405526636,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,24]]},"group-title":"Immunology","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["DP2AI176139"],"award-info":[{"award-number":["DP2AI176139"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32CA921643"],"award-info":[{"award-number":["T32CA921643"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1K99CA296769"],"award-info":[{"award-number":["1K99CA296769"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DGE 2140743"],"award-info":[{"award-number":["DGE 2140743"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Immune aging is being increasingly recognized as a critical barrier to effective cancer immunotherapy, as the aged tumor microenvironment (TME) drives T cell dysfunction and impairs immune control of cancer\n                  <jats:sup>1\u20134<\/jats:sup>\n                  . However, the key molecular drivers of this process as well as potential targets to rescue T cell dysfunction in aged tumors remain incompletely understood. Therefore, we performed in vivo single-cell CRISPR screens in CD8\u207a T cells within aged tumors and tumor-draining lymph nodes (tdLNs). We identified Dusp5 and Zfp219 as key regulators of T cell persistence and effector differentiation in aged hosts. Loss of\n                  <jats:italic>Dusp5<\/jats:italic>\n                  , a negative regulator of ERK signaling, increased ERK1\/2 phosphorylation and enhanced T cell proliferation in both young and aged tumors. In contrast, loss of\n                  <jats:italic>Zfp219<\/jats:italic>\n                  , a transcriptional repressor, induced epigenetic reprogramming of cytotoxic gene programs, thereby increasing granzyme secretion and enhancing antitumor immunity. Moreover, expression of the human ortholog gene\n                  <jats:italic>ZNF219<\/jats:italic>\n                  is increased within intratumoral CD8\u207a T cells in older cancer patients. High\n                  <jats:italic>ZNF219<\/jats:italic>\n                  expression correlates with poorer survival following immune checkpoint blockade (ICB) and reduces persistence of human intratumoral T cells. Notably,\n                  <jats:italic>Zfp219<\/jats:italic>\n                  ablation synergized with anti-PD-1 blockade in mice to expand effector-like CD8\u207a T cells, leading to significantly enhanced anti-tumor immunity and tumor clearance in aged hosts. Together, these findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction and as potential therapeutic targets to rejuvenate T cell antitumor immunity in older cancer patients.\n                <\/jats:p>","DOI":"10.64898\/2026.01.22.701075","type":"posted-content","created":{"date-parts":[[2026,1,25]],"date-time":"2026-01-25T04:20:23Z","timestamp":1769314823000},"source":"Crossref","is-referenced-by-count":1,"title":["CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-5408","authenticated-orcid":false,"given":"Alex C. 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