S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors

Sphingosine-1-phosphate receptor 1 (S1PR1) signaling has been linked to the regulation of immunosuppressive cell populations within the tumor microenvironment (TME); however, its role in shaping anti-tumor CD8⁺ T cell responses remains poorly defined. Herein, we demonstrate that intratumoral CD8⁺ T cells express S1PR1, with expression predominantly enriched in the terminally exhausted subset. Transcriptomic profiling, combined with pharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signaling activates the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)-CHOP (C/EBP homologous protein) axis of the endoplasmic reticulum stress response. CHOP, in turn, upregulates transcription of Map3k13 and Map3k15 , triggering downstream MAPK signaling and culminating in activation of p38MAPK. Activation of this pathway impairs CD8⁺ T cell metabolism and effector function while increasing apoptotic susceptibility. This ultimately limits the persistence and accumulation of functional CD8⁺ T cells within the TME, thereby compromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or its downstream effectors offers a promising strategy to improve cancer immunotherapy outcomes.