Anti-Triggering Receptor Expressed on Myeloid Cells 2-Conjugated Nanovesicles Loaded Vadimezan Reprogram Tumor-Associated Macrophages to Combat Recurrent Lung Cancer

Postoperative lung recurrent cancer exhibited characteristics of an immunosuppressive tumor microenvironment (TME) and low immunogenicity, hindering the therapeutic efficacy of monotherapy, which requires a combination of several treatment modules. Strategies that activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and repolarize tumor-associated macrophages (TAMs) toward the antitumoral M1-like phenotype to reverse the TME are rarely reported. The triggering receptor expressed on myeloid cells 2 (TREM2) is a promising therapeutic target, owing to its critical role in enhancing tumor immunogenicity within the TME. This work describes the design of an anti-TREM2-modified FePt-based biomimetic nanovesicle (FP/Vad@CC-aT2) for the delivery of STING agonist Vadimezan (Vad), which increases tumor immunogenicity to sensitize recurrent lung tumors to immunotherapy. FePt not only acted as a photoacoustic/magnetic resonance imaging contrast agent but also enhanced ferroptosis by catalyzing a Fenton reaction with reactive oxygen species production under X-rays. Simultaneously, anti-TREM2 effectively repolarized TAMs into M1-type macrophages, thereby reversing immunosuppressive TME together with a Vad-activated STING pathway, which promoted the maturation of dendritic cells and enhanced the infiltration of cytotoxic T lymphocytes. Therefore, this study highlighted the FP/Vad@CC-aT2-mediated cascade immune response for suppressing lung cancer recurrence that involves ferroptosis potentiation, TAM repolarization, and STING pathway activation.