Penetrative biomimetic nanovehicle boosts immunotherapy in triple-negative breast cancer via SOS1 blockade

Abstract

Immunotherapy of triple-negative breast cancer (TNBC) is significantly hindered by the immunosuppressive tumor microenvironment (TME). Notably, tumor-associated macrophages (TAMs), which constitute the predominant infiltrating immune cell type in TNBC, represent a critical target for “turning off” immunosuppressive TME. Despite numerous ongoing clinical trials, current strategies exhibit limited efficacy in overcoming immunosuppressive TME. Interestingly, regulation of son of sevenless 1 (SOS1), which is overexpressed in TNBC patients, shows promising potential for TAM repolarization. Herein, we developed a biomimetic liposomal platform (CCM/Cil-lipo@TD), which integrates cilengitide (Cil)-functionalized breast cancer cell membranes (CCM) to co-deliver tetrandrine (TET) and low-dose docetaxel (DTX) for TNBC therapy. This system synergistically enhanced immunotherapy by coupling SOS1 blockade-driven TAM repolarization with immune cell death (ICD)-mediated dendritic cell (DC) maturation, thereby reshaping the highly immunosuppressive TME in TNBC. Critically, the low-density Cil-anchored, CCM-fused liposomes overcome the penetration limitations inherent to conventional CCM-based delivery systems, achieving deep intratumoral accumulation of therapeutic payloads. Mechanistically, the CCM/Cil-lipo@TD ensured that TET-mediated SOS1 inhibition in tumor cells efficiently polarized TAM2 (protumor) toward TAM1 (antitumor). Furthermore, SOS1 blockade synergized with low-dose DTX-induced ICD to remodel TME, as evidenced by sustained cytotoxic T-cell infiltration and suppression of regulatory T cells. The CCM/Cil-lipo@TD exerted superior tumor inhibition (82.9 %) in 4T1 orthotopic models and effectively inhibited postoperative local recurrence and distant metastasis. Taken together, the Cil-engineered, cell membrane-anchoring CCM/Cil-lipo@TD provides a promising approach for TNBC immunotherapy.