USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages

Mincle is essential for tumor-associated macrophage (TAM)-driven cancer progression and represents a potential immuno-therapeutic target for cancer. Nevertheless, the lack of a specific inhibitor has largely limited its clinical translation. Here, we successfully developed a gene therapeutic strategy for silencing Mincle ina virus-free and tumor-specific manner by combining RNA interference technology with an ultrasound-microbub-ble-mediated gene transfer system (USMB). We identified a small hairpin RNA (shRNA) sequence shMincle that can silence not only Mincle expression but also the protumoral effector production in mouse bone marrow-and human THP-1-derived macrophages in the cancer setting in vitro. By using our well-established USMB system (USMB-shMincle), the shMincle-expressing plasmids were delivered in a tissue-specific manner into xenografts of human lung carcinoma A549 and melanoma A375 in vivo. Encouragingly, we found that USMB-shMincle effectively inhibited the protumoral pheno-types of TAMs as well as the progression of both A549 and A375 xenografts in a dose-dependent manner in mice without significant side effects. Mechanistically, we identified that USMB-shMincle markedly enhanced the anticancer M1 pheno-type of TAMs in the A549 and A375 xenografts by blocking the protumoral Mincle/Syk/nuclear factor kappa B (NF-kappa B) signaling axis. Thus, USMB-shMincle may represent a clinically translatable novel and safe gene therapeutic approach for cancer treatment.

Automated summary

The study demonstrates the development of a novel gene therapeutic approach targeting Mincle in a tumor-specific manner using the USMB system. The strategy effectively inhibits protumoral effects in mouse and human macrophages, showing potential for clinical translation in cancer treatment.