Enhancing T-Cell Infiltration and Immunity in Solid Tumors via DNA Nanolinker-Mediated Monocyte Hitchhiking.

Cytotoxic CD8+ T cells are one of the most powerful effectors in the antitumor immune response. However, their insufficient tumor infiltration severely limits the clinical success of immunotherapy in solid tumors. In this work, by using amphiphilic aptamer-incorporated DNA tetrahedra (aptTDN) as the intercellular nanolinker, we developed a monocyte-hitchhiked T-cell delivery strategy to actively promote the intratumoral infiltration of effector CD8+ T cells. Our results demonstrated that membrane-anchoring of aptTDN enabled the specific and stable ligation of T cells with Ly6c+ monocytes, without compromising the migratory behavior of monocytes and the antitumor activity of T cells. By leveraging the intrinsic tumor-homing capability of monocytes, the ligated T cells efficiently accumulated within tumor-associated vasculature and then deeply infiltrated the tumor bed. Additionally, the enhanced intratumoral presence of adoptively transferred effector CD8+ T cells facilitated the establishment of an immunosupportive microenvironment, that further recruited endogenous T cells and ultimately bolstered antitumor immunity. Moreover, our monocyte-hitchhiked T-cell tumor infiltration system could significantly improve the efficacy of immune checkpoint blockade therapy. Collectively, by utilizing chemically synthetic nanolinkers to modulate cellular interactions and develop a delivery system of therapeutic cells, our work presents a new paradigm for the advancement of immunotherapy against solid tumors.