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TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell responses. Constitutive\n                  <jats:italic>\n                    Tmem33\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice exhibited delayed melanoma tumor growth and increased CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell infiltration. Antigen-specific CD8\n                  <jats:sup>+<\/jats:sup>\n                  compartments in tumors of\n                  <jats:italic>\n                    Tmem33\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice showed TCF-1\n                  <jats:sup>+<\/jats:sup>\n                  PD-1\n                  <jats:sup>+<\/jats:sup>\n                  progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells\n                  <jats:italic>ex vivo<\/jats:italic>\n                  , (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of\n                  <jats:italic>ex vivo<\/jats:italic>\n                  -expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower\n                  <jats:italic>TMEM33<\/jats:italic>\n                  expression in patient CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells significantly correlated with improved survival and elevated\n                  <jats:italic>TCF-7<\/jats:italic>\n                  (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>\n                    TMEM33 intrinsically limits progenitor exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, scales anti-tumor responses and predicts melanoma patient survival.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.01.697288","type":"posted-content","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T20:20:14Z","timestamp":1767385214000},"source":"Crossref","is-referenced-by-count":0,"title":["TMEM33 deletion potentiates anti-tumor CD8\n                  <sup>+<\/sup>\n                  T cell immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4916-3719","authenticated-orcid":false,"given":"Matthew T","family":"Jackson","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, UK"},{"name":"Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, UK"},{"name":"Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gusztav","family":"Milotay","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, 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