Faculty, Staff and Student Publications
Publication Date
9-12-2025
Journal
Science Advances
DOI
10.1126/sciadv.adx8134
PMID
40929270
PMCID
PMC12422196
PubMedCentral® Posted Date
9-10-2025
PubMedCentral® Full Text Version
Post-print
Abstract
PTDSS1 (phosphatidylserine synthase 1) encodes an enzyme that facilitates production of phosphatidylserine (PS), which mediates a global immunosuppressive signal. Here, based on in vivo CRISPR screen, we identified PTDSS1 as a target to improve anti-PD-1 therapy. Depletion of Ptdss1 in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including B2m, Cxcl9, Cxcl10, and Stat1, even in the absence of IFN-γ stimulation in vitro. Loss of Ptdss1 in tumor cells also led to increased expression of MHC-I, enhanced cytotoxicity of CD8+ T cells, and increased frequency of an iNOS+ myeloid subset. A gene signature derived from the iNOS+ myeloid cell subset correlated with clinical benefit in patients treated with anti-PD-1 therapy. Moreover, genetic and pharmacological inhibition of Ptdss1 in different tumor models improved anti-PD-1 therapy. Together, our results provide insights on a therapeutic strategy for overcoming immunosuppression by inhibiting PTDSS1 and provide rationale for development of a combination immunotherapy strategy composed of PTDSS1 inhibition plus PD-1 blockade.
Keywords
Humans, Animals, Programmed Cell Death 1 Receptor, Mice, Cell Line, Tumor, Neoplasms, Immune Checkpoint Inhibitors, CD8-Positive T-Lymphocytes, Interferon-gamma, Immunotherapy, Phosphatidylserines, Gene Expression Regulation, Neoplastic
Published Open-Access
yes
Recommended Citation
Liu, Jielin; Herbrich, Shelley; Basu, Sreyashi; et al., "Loss of PTDSS1 in Tumor Cells Improves Immunogenicity and Response to Anti-PD-1 Therapy" (2025). Faculty, Staff and Student Publications. 4999.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4999
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