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

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.