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.