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SMS2 siRNA inhibits pancreatic tumor growth by tumor microenvironment modulation

Xin Jiang1, Ziqing Yuan2, Tingbo Ding2

  • 1Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, China.

International Immunopharmacology
|September 10, 2024
PubMed

Insights

Targeting sphingomyelin synthase 2 (SMS2) with siRNA gene therapy can reduce immune cell infiltration in pancreatic cancer. This approach suppresses tumor growth and improves the tumor microenvironment for potential pancreatic cancer treatment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits significant treatment resistance due to suppressor immune cell infiltration in the tumor microenvironment (TME).
  • Sphingomyelin synthase 2 (SMS2) plays a key role in sphingolipid metabolism and plasma membrane integrity.

Purpose of the Study:

  • To develop and evaluate a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery.
  • To investigate the therapeutic potential of SMS2 inhibition in a pancreatic cancer model.

Main Methods:

  • Development of a self-assembling plasmid encoding SMS2 siRNA for targeted gene silencing.
  • In vivo administration of SMS2 siRNA in a murine Panc02 pancreatic carcinoma model.
  • Analysis of tumor growth, immune cell polarization (TAMs), immune cell infiltration (TANs), and associated signaling pathways (NF-κB/CXCL5).

Main Results:

  • SMS2 siRNA specifically inhibited SMS2 expression while sparing SMS1.
  • Administration of SMS2 siRNA suppressed tumor growth in the murine model.
  • SMS2 siRNA modulated tumor-associated macrophage polarization and reduced tumor-associated neutrophil infiltration.
  • The NF-κB/CXCL5 pathway was implicated in the observed immunomodulatory effects.

Conclusions:

  • Targeting SMS2 with siRNA represents a viable strategy to overcome treatment resistance in pancreatic cancer.
  • Modulating the immunosuppressive TME via SMS2 inhibition holds promise for pancreatic cancer therapy.
Keywords:
CXCL5Pancreatic cancerSMS2SiRNATumor microenvironment

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