Background <p>Despite the success of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, its efficacy against solid tumors like non-small cell lung cancer (NSCLC) remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient T-cell infiltration. Dendritic cell (DC) vaccines offer potential to remodel the TME but face challenges with targeted antigen delivery. Therefore, we want to develop a DC-targeted nanovesicle (NV) vaccine to enhance the antitumor activity of CAR-T cells against lung cancer.</p> Results <p>We engineered CD205-targeted nanovesicles (aCD205 NVs) derived from LLC cells displaying anti-CD205 single-chain variable fragments. These NVs were evaluated for DC targeting, maturation induction, and T cell priming in vitro and were injected intravenously with Poly(I: C) as a DC vaccine to reprogram the TME in vivo. The combinatorial effect with mesothelin (MSLN)-targeted CAR-T cells (CAR-T + Vac therapy) was assessed in subcutaneous and orthotopic murine LLC models. We found that CAR-T + Vac therapy significantly enhanced tumor infiltration of CAR-T cells and endogenous T cells, substantially elevated cytotoxic molecules (Granzyme B and Perforin), and pro-inflammatory cytokines (IFN-γ and TNF-α), while reducing immunosuppressive cell populations (M2 macrophages, MDSCs, and Tregs) and IL-10. This synergistic remodeling resulted in potent tumor suppression and markedly prolonged overall survival, with no observable short-term toxicity.</p> Conclusions <p>This study establishes a novel combinatorial strategy utilizing CD205-targeted, tumor cell-derived NVs as a DC vaccine to effectively reprogram the immunosuppressive TME. CAR-T + Vac therapy significantly enhances CAR-T cell infiltration and antitumor efficacy against lung cancer, providing a versatile and promising platform for advancing solid tumor immunotherapy.</p> Graphical Abstract <p></p>