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Updated: Sep 23, 2025

Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
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Overcoming resistance to oncolytic virus M1 by targeting PI3K-γ in tumor-associated myeloid cells

Yang Liu1, Cuiying Xu1, Xiaoting Xiao1

  • 1Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|May 13, 2022
PubMed

Insights

Oncolytic virus M1 (OVM) can be blocked by tumor-associated myeloid cells (TAMCs). Targeting TAMCs with PI3K-γ inhibitors enhances OVM efficacy and long-term antitumor immunity.

Area of Science:

  • Immunology
  • Virology
  • Oncology

Background:

  • Oncolytic viruses (OVs) show promise as cancer immunotherapies.
  • Treatment resistance to OVs is a significant clinical challenge.
  • Understanding immunosuppressive mechanisms is crucial for improving OV therapy.

Purpose of the Study:

  • To investigate the role of tumor-associated myeloid cells (TAMCs) in OVM resistance.
  • To elucidate the molecular mechanisms by which TAMCs suppress OV antitumor effects.
  • To identify strategies to overcome TAMC-mediated immunosuppression and enhance OV efficacy.

Main Methods:

  • Utilized oncolytic virus M1 (OVM) in preclinical cancer models.
  • Analyzed TAMC infiltration and phenotype modulation by OVM.
  • Investigated the role of interleukin-6 (IL-6) and the PI3K-γ/Akt pathway in TAMC activation.
  • Pharmacologically inhibited PI3K-γ and combined OVM with immune checkpoint antibodies.

Main Results:

  • OVM treatment led to increased TAMC infiltration and enhanced immunosuppressive phenotypes.
  • OVM-treated tumor cells secreted IL-6, activating the PI3K-γ/Akt axis in TAMCs.
  • This activation promoted TAMC infiltration and suppressed cytotoxic CD8+ T lymphocytes.
  • Pharmacological inhibition of PI3K-γ reversed TAMC-mediated immunosuppression and boosted OVM efficacy.
  • Combination therapy with OVM, PI3K-γ inhibitors, and immune checkpoint antibodies eradicated refractory tumors and induced immune memory.

Conclusions:

  • TAMCs act as a significant barrier to OVM efficacy by inducing immunosuppression.
  • OVM's efficacy is modulated by TAMCs, highlighting its dual role in antitumor immunity.
  • Targeting the PI3K-γ/Akt pathway in TAMCs is a viable strategy to enhance OV therapy.
  • Combination strategies involving OVM, PI3K-γ inhibition, and immune checkpoint blockade hold potential for treating refractory solid tumors.
Keywords:
CD8(+) T cellsPI3Kantitumor immunitymyeloid cellsoncolytic virustumor microenvironment

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