<p>T cell lymphomas constitute approximately 10% of all non-Hodgkin lymphomas and are associated with poor prognosis. Patients experiencing early relapse post-treatment exhibit a 5-year overall survival rate of 11%, underscoring the need for improved therapeutic strategies. The clonality of T cell cancers makes the T cell receptor (TCR) an appealing target for immunotherapy. Here, we developed and evaluated a synDNA vaccine against the TCR⍺, β, and γ chains (TCRfullvax) of the EL4 murine T cell lymphoma model. Immunogenicity studies revealed induction of robust T cell responses against all three TCR chains, with identification of immunodominant epitopes for each chain. Notably, we observed no significant differences in the number of live T cells between TCRfullvax-vaccinated group and control groups, indicating the vaccine's ability to selectively break tolerance against vaccinated TCR without broadly depleting T cells. In a minimal residual disease model, TCRfullvax delayed EL4 tumor progression. Tumors from TCRfullvax-treated mice revealed downregulation of TCR expression, suggesting a potential immune escape mechanism. Neoantigens, derived from somatic mutations within tumor genome, present another promising target for anticancer vaccine development, accordingly we developed a second vaccine targeting 15 neoantigens identified through sequencing of EL4 cells (EL4neovax). EL4neovax elicited strong immune responses against 5/15 encoded neoantigens and controlled EL4 tumors. Co-administration of TCRfullvax and EL4neovax demonstrated superior tumor control compared to either vaccine design alone, further supporting that neoantigen targeting can partially mitigate TCR loss. These findings highlight the potential of combining TCR-targeted and neoantigen-based immunotherapies for the treatment of T cell lymphomas. Further investigation of this dual-vaccine approach is warranted to optimize the therapeutic efficacy for this difficult disease.</p>