The noncanonical function of S1PR1 in mediating CD8+ T cell dysfunction in tumor
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, wedemonstrate that intratumoral CD8+ T cells express S1PR1, with expression predominantlyenriched in the terminally exhausted subset. Transcriptomic profiling, combined withpharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signalingactivates the PERK-CHOP axis of the endoplasmic reticulum stress response. CHOP, in turn,upregulates transcription of Map3k13 and Map3k15, triggering downstream MAPK signalingand culminating in activation of p38MAPK. Activation of this pathway impairs CD8+T cellmetabolism and effector function while increasing apoptotic susceptibility. This ultimatelylimits the persistence and accumulation of functional CD8+ T cells within the TME, therebycompromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or itsdownstream effectors offers a promising strategy to improve cancer immunotherapyoutcomes.