Alapan, Y.; Kim, J.; Min, K.; Shih, A.; Lucas, S. N.; Yoon, T.; Archer, P. A.; Lin, H. K.; Freeman, R.; Wittling, M. C.; Wyatt, M.; Paulos, C. M.; Rafiq, S.; Thomas, S. N.

T cell immune checkpoint expression and dysfunction are attributed solely to molecular cues. We discover using microphysiological systems and in vivo models that transmigration through confined pores induces acute loss of programmed cell death 1 within minutes of surface immune checkpoint markers on CD8+ T cells through ubiquitin-mediated proteasomal degradation, corresponding with enhanced fitness and function. Such imprints and its underlying mechanism of programmed cell death 1 loss are conserved across species and applicable to human TIL and CAR T cells, and are correlative with disease outcomes in human melanoma. Our findings establish the diverse tissues landscapes that T cells traverse during immunosurveillance, and specifically transmigration, as a form of mechanical immune regulation, and reveal a mechano-modulatory strategy to improve the quality and persistence of engineered or patient-derived T cells for adoptive immunotherapy.