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

Abstract

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.