Tumor targeting dendritic nanocarrier with immunogenic cell death inducing and TIGIT blockade for synergistic chemo-immunotherapy against TNBC.

The clinical therapeutic effect of immune-checkpoint blockade (ICB) on triple-negative breast cancer (TNBC) is limited due to low tumor immunogenicity and tumor immunosuppressive microenvironment. Combination therapies of chemotherapy and ICB have been confirmed efficacious. Herein, poly(L-lysine) dendrimer (PLLD) nanosphere (PR-T@PLLD) integrating chemotherapeutic drug paclitaxel (PTX), natural anti-tumor compound Rubioncolin C (RC) and TIGIT/PVR blocking peptide (D)TBP-3 is constructed for chemo-immunotherapy of anti-PD-1 resistant tumor. The PEGylation and (D)TBP-3 modification endow PR-T@PLLD with prolonged blood circulation, enhanced tumor penetration and improved internalization. In the acidic environment of lysosomes, PR-T@PLLD disassembles and releases PTX, RC and (D)TBP-PLLD. The cell death induced by PTX is significantly enhanced through synergy with RC. RC collaborated PTX also triggers robust immunogenic cell death that efficiently increases tumor infiltration of cytotoxic T lymphocytes (CTLs). Additionally, the released (D)TBP-PLLD inhibits the exhaustion of CTLs via directly binding to TIGIT and blocking the interaction of TIGIT with its ligand PVR. Thus, PR-T@PLLD arouses a conspicuous anti-tumor immune response via increasing income and reducing expenditure of CTLs. Moreover, PR-T@PLLD reduces the recruitment of immunosuppressive cells in tumor. PR-T@PLLD also inhibits tumor metastasis through evoking immune memory response and inhibiting epithelial-mesenchymal transition and extracellular matrix degradation. In general, PR-T@PLLD is a promising nanoplatform realizing synergistic enhancement of chemo-immunotherapy against anti-PD-1 resistant TNBC.