Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti–PD-1 therapy

<i>PTDSS1</i> (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 <i>Ptdss1</i> in tumor cells increased expression of interferon-γ (IFN-γ)-regulated genes, including <i>B2m</i>, <i>Cxcl9</i>, <i>Cxcl10</i>, and <i>Stat1</i>, even in the absence of IFN-γ stimulation in vitro. Loss of <i>Ptdss1</i> 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 <i>Ptdss1</i> 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.