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Abstract Triple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks estrogen receptor, progesterone receptor, and HER2 expression, which limits the efficacy of targeted therapies. MicroRNA‐34a‐5p (miR‐34a), a tumor‐suppressor miRNA known for regulating oncogenic pathways, initially appeared promising as a therapeutic avenue. However, the clinical translation of miR‐34a has been hindered by challenges such as poor stability, inefficient cytoplasmic delivery, and immune‐related toxicities, as evidenced by the failure of MRX34 in trials. To address these limitations, this study developes a novel antibody‐oligonucleotide conjugate (AOC) platform anti‐CD47‐miR‐34a conjugate (aCD47‐C‐miR34a). The aCD47‐C‐miR34a system combines the anti‐CD47 antibodies with miR‐34a using a bioreducible linker, ensuring targeted cytoplasmic delivery via CD47‐mediated endocytosis and endosomal escape. CD47, an immune checkpoint protein overexpressed in TNBC, facilitates immune evasion, making it an attractive therapeutic target. In preclinical TNBC models, aCD47‐C‐miR34a successfully restored miR‐34a's tumor‐suppressive functions by downregulating oncogenic pathways including PD‐L1, while modulating the tumor microenvironment. This dual mechanism promoted macrophage phagocytosis, enhanced CD8 + T‐cell activation, and induced apoptosis, resulting in significant tumor inhibition without systemic toxicity. These findings demonstrate the transformative potential of aCD47‐C‐miR34a in overcoming TNBC's oncogenic and immune‐evasive mechanisms, paving the way for innovative treatments in TNBC and other heterogeneous, aggressive cancers.
Ryu et al. (Tue,) studied this question.