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  3. In situ-formed immunotherapeutic hydrogel containing sphingosine-1-phosphate for enhanced lung cancer immunotherapy

In situ-formed immunotherapeutic hydrogel containing sphingosine-1-phosphate for enhanced lung cancer immunotherapy

  • Sci Adv. 2025 Aug 8;11(32):eadw5001. doi: 10.1126/sciadv.adw5001.
Hui Shen 1 2,  Qi Deng 3,  Zhike Chen 2 4,  Qiang Zhang 2 5,  Xiao Zhou 1,  Qian Chen 2,  Jiang Fan 1
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200086, China.
  • 2 Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
  • 3 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
  • 5 School of Materials Science and Engineering, Tongji University, Shanghai 201804, China.
PMID: 40779634 DOI: 10.1126/sciadv.adw5001
Abstract

Limited infiltration of immune cells within tumors restricts the therapeutic efficiency of immune checkpoint blockades. Herein, we discover that sphingosine-1-phosphate (S1P) is down-regulated in patients with lung Cancer who do not respond to PD-1/PD-L1 therapy. Our findings indicate that S1P gradient enhances the migration and viability of immune cells and promotes the polarization of macrophages toward the M1 phenotype primarily through mitochondrial reactive oxygen species-activated nuclear factor κB and Janus kinase-signal transducers and activators of transcription signaling pathways. To capitalize on these findings, we used a biodegradable sodium alginate hydrogel as a delivery system for the sustained and sequential release of S1P and anti-PD-L1 (αPDL1). In vivo studies demonstrated that S1P-αPDL1@Gel effectively inhibited tumor growth and reduced the recurrence of local tumors after surgery. Additionally, the hydrogel significantly enhanced the infiltration of dendritic cells, M1 macrophages, CD4+ T cells, and CD8+ T cells. S1P-αPDL1@Gel holds a promising therapeutic strategy for remodeling the immunosuppressive tumor microenvironment.

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