ABSTRACT: Tumor-derived microparticles (TMPs), a subtype of extracellular vesicles, hold great promise in tumor immunotherapies and vaccines, and have demonstrated significant potential as drug delivery systems for clinical tumor treatment. In our previous study, we utilized TMPs released from parental tumor cells upon ultraviolet irradiation (UV-TMPs) to deliver methotrexate (MTX), effectively managing malignant pleural effusion (MPE) in advanced lung cancer cases. However, concerns remain regarding the potential risks associated with nucleic acid incorporation, alongside the limited antitumor efficacy of UV-TMPs alone. Here, we introduce a microwave (MW)-assisted method for preparing TMPs, termed MW-TMPs. Brief exposure to short-wavelength MW radiation triggered various forms of programmed cell death, including apoptosis, necroptosis, and pyroptosis, promoting the release of TMPs. These resulting MW-TMPs contained fewer nucleic acids and exhibited superior antitumor activity in vivo compared to UV-TMPs. Mechanistically, MW-TMPs induced immunogenic cell death (ICD) by shuttling HMGB1 and enabled dual targeting of tumor cells by natural killer (NK) and T cells, while reprogramming of suppressive tumor immune microenvironments in LLC lung adenocarcinoma (LUAD) mouse models. Furthermore, similar effective tumor inhibition was observed in clinical MPE samples and zebrafish PDX models, suggesting the potential of MW-TMPs for clinical cancer immunotherapy. In further application studies, MW-TMPs successfully encapsulated the chemotherapeutic drug MTX, demonstrating enhanced antitumor efficacy both in vitro and in vivo, thereby establishing their potential as an innovative drug delivery platform. Moreover, combination immunotherapy with PD-L1 blockade confirmed a synergistic antitumor effect. This MW-TMP development strategy has improved upon traditional UV-TMP methods in terms of simplicity, efficiency, safety, and efficacy.
