In vivo-edited CCR7⁺IL-7⁺ DCs reverse T cell exhaustion by promoting T memory stem cell differentiation

T cell exhaustion presents a challenge for antitumor immunotherapy. T memory stem cells (Tscms), whose ability to self-renew can continuously generate effector T cells, offering a way to reverse T cell exhaustion. Here, we propose a Tscm regulation strategy involving the construction of dendritic cell (DC)-targeting CCR7/IL-7 mRNA liposomes to edit CCR7⁺IL-7⁺ DCs in vivo, thus directly promoting Tscm differentiation within tumor-draining lymph nodes (TDLNs). The antigen-presenting CCR7⁺IL-7⁺ DCs migrate to the T-zone within TDLNs via CCR7-mediated signaling and secrete IL-7 to induce naive T cells to differentiate into Tscms. The antigens activate Tscms, promoting continuous Tscm self-renewal and effector T cell generation. The powerful antitumor effects have been observed in B16F10 and 4T1 tumor-bearing mice, and 80% of the mice exhibited suppressed distant tumor formation in the B16F10 prevention model. Overall, this research highlights the importance of Tscm abundance for antitumor immunotherapy and provides high clinical value for developing cancer vaccines.