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tRNA-Derived Small RNA Accelerates Tumorigenesis through Crosstalk with Tumor-Associated Macrophages, and

Zhou Zhou1, Bairong Chen1, Jibin Liu2

  • 1Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China.

ACS Applied Materials & Interfaces
|July 8, 2025
PubMed

Insights

This study reveals how tRNA-derived small RNA (tsRNA) tsr_019759 promotes hepatocellular carcinoma (HCC) by interacting with M2 tumor-associated macrophages (TAMs). A novel nanoparticle delivery system effectively inhibited HCC progression in mouse models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • TRNA-derived small RNAs (tsRNAs) are implicated in various cancers.
  • The tumor microenvironment (TME) significantly influences hepatocellular carcinoma (HCC) progression.
  • The specific roles of tsRNAs within the HCC TME remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the mechanism by which tsRNAs contribute to HCC development within the TME.
  • To investigate the role of tsr_019759 in HCC progression and its interaction with tumor-associated macrophages (TAMs).
  • To develop and evaluate a novel therapeutic strategy for HCC targeting tsr_019759.

Main Methods:

  • Quantification of tsr_019759 expression in HCC.
  • Investigation of tsr_019759's effects on HCC cell growth, metastasis, and signaling pathways (JAK2/STAT3, DR3/NF-κB).
  • Assessment of tsr_019759's impact on TAM polarization and exosome secretion.
  • Construction and evaluation of cancer cell membrane-coated nanoparticles (in-tsr/PEI/PLGA@CCM) for HCC treatment in vivo.

Main Results:

  • tsr_019759 was significantly upregulated in HCC and promoted tumor growth and metastasis by inhibiting TNFSF15 and activating JAK2/STAT3.
  • tsr_019759 induced M2 TAM polarization by impeding TNFSF15 secretion and inhibiting the DR3/NF-κB pathway.
  • M2 TAMs further promoted HCC via EGF secretion and EGFR/JAK2/STAT3 activation.
  • The developed nanocomposite (in-tsr/PEI/PLGA@CCM) effectively suppressed HCC progression by disrupting HCC-TAM crosstalk in mouse models.

Conclusions:

  • tsr_019759 accelerates HCC progression by enhancing crosstalk with M2 TAMs within the TME.
  • The study elucidates a novel molecular mechanism involving tsr_019759, TNFSF15, TAMs, and JAK/STAT signaling in hepatocarcinogenesis.
  • The targeted nanoparticle delivery system in-tsr/PEI/PLGA@CCM shows promise as a therapeutic strategy for HCC.
Keywords:
TNFSF15hepatocellular carcinomahsa_tsr019759nanotherapytumor-associated macrophages

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