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Gene Therapy00:59

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A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies
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Targeting severe acidity for tumor-activatable Interleukin-2 therapy.

Qiang Feng1, Raymundo Pantoja2, Jacqueline G Lopez3

  • 1Department of Biomedical Engineering, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Cell Reports. Medicine
|January 21, 2026
PubMed
Summary
This summary is machine-generated.

A novel nanoparticle system activates Interleukin-2 (IL-2) specifically in tumors by utilizing ultra pH-sensitive polymers. This approach reduces systemic toxicity and enhances cancer immunotherapy effectiveness.

Keywords:
cancer immunotherapycytokine therapyimmune engineeringimmune-related toxicityinterleukin-2pH-sensitive nanoparticle

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Area of Science:

  • Biotechnology
  • Immunotherapy
  • Materials Science

Background:

  • Interleukin-2 (IL-2) shows promise in cancer immunotherapy but has a narrow therapeutic window, limiting its clinical application.
  • Existing strategies like IL-2-Fc fusion proteins and covalent prodrugs face challenges with systemic toxicity, potency compromise, and applicability.
  • Tumor-specific activation of IL-2 is crucial for improving its therapeutic index.

Purpose of the Study:

  • To develop a non-covalent nanoparticle system for tumor-specific activation of IL-2 using ultra pH-sensitive (UPS) polymers.
  • To evaluate the safety and efficacy of the UPS/IL-2-Fc nanoparticle in reducing systemic toxicity while maintaining antitumor activity.
  • To elucidate the mechanisms underlying the protective effects of the pH-triggered IL-2 activation.

Main Methods:

  • Formulation of nanoparticles using clinically validated ultra pH-sensitive (UPS) polymers and IL-2-Fc.
  • Assessment of nanoparticle stability and dissociation at physiological and tumor-specific acidic pH.
  • Evaluation of systemic toxicity markers (e.g., interferon-γ, vascular leak syndrome) and antitumor efficacy in preclinical models.

Main Results:

  • The UPS/IL-2-Fc nanoparticle remained stable at physiological pH but dissociated and activated IL-2 at acidic tumor pH (< 5.3).
  • This pH-triggered activation significantly reduced circulating interferon-γ (over 100-fold) and prevented vascular leak syndrome.
  • Antitumor efficacy was preserved, demonstrating the therapeutic potential of targeted IL-2 delivery.
  • Mechanistic studies indicated that pH-dependent shielding and macrophage clearance contributed to the protective effect.

Conclusions:

  • A non-covalent, pH-sensitive nanoparticle system enables tumor-specific activation of IL-2, overcoming limitations of traditional approaches.
  • This bioengineering strategy significantly reduces systemic toxicity associated with IL-2 immunotherapy.
  • The UPS/IL-2-Fc nanoparticle represents a promising platform for enhancing cancer immunotherapy with a broader therapeutic window.