STING stimulation via supramolecular prodrug hydrogel boosts innate-adaptive immune cross-talk to prevent glioblastoma recurrence

Sep 30, 2026

Glioblastoma multiforme (GBM) shows persistent resistance to immunotherapy due to a strongly immunosuppressive tumor microenvironment and limited T cell infiltration. This study engineers a STING agonist–incorporated prodrug hydrogel that forms in situ during tumor resection, acting as a sustained drug depot. The hydrogel reprograms the microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cells, and enhancing cytotoxic T lymphocyte infiltration, thereby generating robust antitumor immunity, inhibiting postoperative recurrence, extending animal survival, and inducing durable immune memory.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Glioblastoma recurrence and immunosuppressive microenvironment

STING activation in innate and adaptive immunity

Need for improved delivery of STING agonists

Prodrug hydrogel strategy and rationale

HEALTH AND MEDICINE STING stimulation via supramolecular prodrug hydrogel boosts innate-adaptive immune cross-talk to prevent glioblastoma recurrence Qi Shang1, Chenwei Jiang1, Mingmei Guo1, MingluTang1, Jiapei Yang1, Junjie Xie2, Xiaoran An1, Qiang Zhang3, Feihu Wang1* Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, demonstrates persistent resistance to immunotherapy due to its profoundly immunosuppressive microenvironment and markedly limited T cell infiltration. In this context, we engineered a STING agonist–incorporated prodrug hydrogel that orchestrates dual activation of innate and adaptive immunity to prevent postoperative GBM recurrence. We found that this in situ–forming hydrogel integrates seamlessly with tumor resection procedures, serves as a drug depot for sustained tumoral releases of therapeutic agents, and thus reprograms the tumor microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cell activity, and enhancing cytotoxic T lymphocyte infiltration, thereby establishing a robust antitumor immune response. As a postoperative adjuvant therapy, the hydrogel effectively inhibits orthotopic GBM recurrence and extends animal survival while establishing durable immune memory against tumor rechallenge. Our findings demonstrate the translational potential of immunologically engineered hydrogels for STING-activated immunotherapy in preventing postresection GBM recurrence. copyright © 2026 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. no claim to original U.S. Government Works. distributed under a creative commons Attribution noncommercial license 4.0 (cc BY-nc) . INTRODUCTION Glioblastoma multiforme (GBM) is recognized as the highly aggressive and treatment-refractory primary malignant brain tumor (1, 2) . Despite comprehensive treatment involving maximal surgical resection followed by adjuvant radiotherapy and chemotherapy, more than two-thirds of GBM cases experience peri-cavitary recurrence (3–5), highlighting the urgent need for more effective therapeutic strategies. Although immunotherapy has revolutionized treatment for several advanced cancers, brain tumors remain a notable exception to this therapeutic progress (6–8). Through the analysis of Gene Expression Omnibus (GEO) datasets, we identified distinct gene expression profiles in GBM compared to those in normal tissues (fig. S1). Notably, we observed up-regulated genes were significantly enriched in pathways associated with negative regulation of both innate and adaptive immune responses (Fig. 1, A and B) . Immune profiling demonstrated predominant tissue-resident macrophages and limited adaptive immune cells in GBM (GSM397636) relative to normal tissue (GSE397658) (Fig. 1C) . Specifically, GBM tissues exhibited abundant immunosuppressive populations [such as M2 macrophages and regulatory T (Treg) cells] but were deficient in CD8+ T cells (Fig. 1, D to F), fostering an immunosuppressive microenvironment that promotes tumor progression and recurrence (9–12). These findings suggest that modulating immunosuppressive cell depletion while enhancing CD8+ T cell infiltration may restore antitumor immunity and prevent postoperative recurrence. Emerging evidence indicates that stimulator of interferon genes (STING) pathway activation potently enhances both innate and adaptive immune responses within the tumor microenvironment 1School of Biomedical engineering, Shanghai Jiaotong University, Shanghai 200240, PR china. 2School of chemistry and chemical engineering, Shanghai Jiao tong University, Shanghai 200240, PR china. 3Beijing Key laboratory of Molecular Pharmaceutics and new drug delivery Systems, State Key laboratory of natural and Biomimetic drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR china. *[corresponding author. email:](corresponding author. email:) [fhwang21@sjtu.edu.cn](fhwang21@sjtu.edu.cn) [

FAQs

Why is immunotherapy less effective in glioblastoma?

GBM maintains strong immunosuppression in its microenvironment and shows markedly limited CD8+ T cell infiltration, supporting recurrence despite treatment.

How does the engineered STING agonist–incorporated hydrogel work?

The in situ–forming hydrogel integrates with tumor resection, provides sustained drug release, promotes M1 macrophage polarization, suppresses regulatory T cell activity, and enhances cytotoxic T cell infiltration.

What therapeutic outcome does the hydrogel achieve after surgery?

As a postoperative adjuvant, it inhibits orthotopic GBM recurrence, extends animal survival, and establishes durable immune memory against tumor rechallenge.

Sep 30, 2026

Uploaded by Indoniesian Boy