RT Journal Article SR Electronic T1 Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e004695 DO 10.1136/jitc-2022-004695 VO 10 IS 7 A1 Rita C. Acúrcio A1 Sabina Pozzi A1 Barbara Carreira A1 Marta Pojo A1 Nuria Gómez-Cebrián A1 Sandra Casimiro A1 Adelaide Fernandes A1 Andreia Barateiro A1 Vitor Farricha A1 Joaquim Brito A1 Ana Paula Leandro A1 Jorge A R Salvador A1 Luís Graça A1 Leonor Puchades-Carrasco A1 Luís Costa A1 Ronit Satchi-Fainaro A1 Rita C. Guedes A1 Helena F. Florindo YR 2022 UL http://jitc.bmj.com/content/10/7/e004695.abstract AB Background Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents.Methods In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function.Results Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy.Conclusions We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.All data relevant to the study are included in the article or uploaded as supplementary information.