tRNA-Derived Small RNA Accelerates Tumorigenesis through Crosstalk with Tumor-Associated Macrophages, and Downregulation with Cell Membrane-Modified Polymer Nanoparticles Enables Treatment Response

Abstract Accumulating evidence has shown that tRNA-derived small RNAs (tsRNAs) play pivotal roles in the progression of the majority of malignancies. The tumor microenvironment (TME) is important for hepatocellular carcinoma (HCC) progression. However, how tsRNAs exert their effects through the TME to drive hepatocarcinogenesis is unclear. We revealed that tsr_019759, a tsRNA, was significantly upregulated in HCC, and it promoted HCC growth and metastasis via inhibiting TNFSF15 expression and activating the JAK2/STAT3 signal pathway. Moreover, tsr_019759 could impede the exocrine secretion of TNFSF15, thereby inducing tumor-associated macrophage (TAM) polarization toward the M2 type through inhibiting the DR3/NF-κB signaling pathway. Additionally, M2 TAMs further facilitated HCC development through increasing EGF secretion and activating the EGFR/JAK2/STAT3 signaling pathway. Furthermore, a type of delivery system targeting inhibition of tsr_019759 loaded in HCC cancer cell membrane (CCM)-packed polyethylenimine (PEI)-modified poly lactic-co-glycolic acid (PLGA) nanoparticles, namely, in-tsr/PEI/PLGA@CCM, was constructed. These nanocomposites effectively arrested HCC progression by blocking the reciprocal crosstalk between HCC cells and M2 TAMs in both subcutaneous xenograft and orthotopic tumor mouse models. Taken together, this study highlights the potential molecular mechanisms of tsr_019759 accelerating HCC progression through boosting the interaction with M2 TAMs in the TME. Moreover, in-tsr/PEI/PLGA@CCM may be a promising treatment strategy for this deadly disease.