TMEM33 deletion potentiates anti-tumor CD8 ⁺ T cell immunity

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. 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⁺ T cell responses. Constitutive <i>Tmem33</i> ^<i>-/-</i> mice exhibited delayed melanoma tumor growth and increased CD8⁺ T cell infiltration. Antigen-specific CD8⁺ compartments in tumors of <i>Tmem33</i> ^<i>-/-</i> mice showed TCF-1⁺PD-1⁺ 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⁺ T cells <i>ex vivo</i>, (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 <i>ex vivo</i>-expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower <i>TMEM33</i> expression in patient CD8⁺ T cells significantly correlated with improved survival and elevated <i>TCF-7</i> (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8⁺ T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy.