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Strategies to enhance the longevity of both populations remain scarce. Here, we demonstrate that ablation of UBE2F, a neddylation E2 enzyme, induces a resilience program in CD8 T cells that operates across both TMEM and TEX compartments, resulting in improved viral and tumor control. This resilience state is characterized by enhanced self-renewal and survival without perturbing the conventional CD8 T cell differentiation trajectories. Mechanistically, UBE2F deficiency inhibited neddylation of CUL5, leading to accumulation of JUNB and upregulation of IL-2R\u03b2. The increased IL-2R\u03b2 expression hypersensitizes CD8 T cells to physiological IL-15, thereby conferring the resilience features. Together, these findings identify the UBE2F\u2013CUL5\u2013JUNB\u2013IL-2R\u03b2 axis as a conserved posttranslational mechanism regulating CD8 T cell longevity across memory and exhausted states, providing a novel strategy for enhancing antiviral and antitumor immunity.<\/jats:p>","DOI":"10.1084\/jem.20252687","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T06:23:14Z","timestamp":1776838994000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting UBE2F induces a resilience program enhancing CD8 T cell immunity"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7048-1966","authenticated-orcid":true,"given":"Xiaonan","family":"Ma","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cve4549","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of Molecular Oncology, Institute for Immunology, Beijing 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