Specifically, the researchers found that PTDSS1 deficiency not only enhanced tumor cells' responsiveness to interferon-γ (IFN-γ) but also increased antigen presentation (e.g., elevated MHC-I expression), making tumor cells more susceptible to antigen-specific CD8+ T cell recognition and killing. Furthermore, PTDSS1 deficiency improved the tumor microenvironment (TME), increasing the number of tumor-infiltrating CD8+ T cells and the frequency of iNOS-positive myeloid cells. Genetic and pharmacological interventions confirmed that both PTDSS1 knockdown and PTDSS1 inhibitors enhanced the efficacy of PD-1 inhibitors, suppressed tumor burden, and prolonged overall survival in mice. The related research was published in Science Advances.
To identify strategies to enhance the efficacy of ICIs, researchers used the MB49 bladder cancer cell line, which is poorly responsive to immune checkpoint inhibitors (ICIs), and conducted an in vivo CRISPR-Cas9 gene knockout screen. The goal was to identify key genes that could enhance the efficacy of PD-1 inhibitors. After screening 2,013 genes, the researchers not only identified several genes known to be associated with immunotherapy (such as the antigen presentation genes B2m and H2-k1) and genes known to synergize with ICIs (such as Cdk4 and Pikfyve), but also identified a new key gene, PTDSS1, that influences the efficacy of PD-1 inhibitors.
| Cat.No. | Product Name | Price |
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| CSC-DC012649 | Panoply™ Human PTDSS1 Knockdown Stable Cell Line | Inquiry |
| CSC-SC012649 | Panoply™ Human PTDSS1 Over-expressing Stable Cell Line | Inquiry |
| AD13127Z | Human PTDSS1 adenoviral particles | Inquiry |
| LV23013L | human PTDSS1 (NM_014754) lentivirus particles | Inquiry |
| CDFH015455 | Human PTDSS1 cDNA Clone(NM_014754.1) | Inquiry |
| CDFR002540 | Rat Ptdss1 cDNA Clone(NM_001012113.1) | Inquiry |
| MiUTR1H-08410 | PTDSS1 miRNA 3'UTR clone | Inquiry |
| MiUTR1R-06169 | PTDSS1 miRNA 3'UTR clone | Inquiry |
Next, to validate the function of PTDSS1, the researchers generated PTDSS1 knockdown in MB49 and B16F10 cell lines and evaluated its effect on the efficacy of PD-1 inhibitors in mouse models. The results showed that PTDSS1 knockdown significantly enhanced the efficacy of PD-1 inhibitors, as evidenced by reduced tumor burden and prolonged survival in mice.
In addition, the researchers conducted pharmacological intervention studies. The results showed that the use of the PTDSS1 small molecule inhibitor DS55980254 can also enhance the efficacy of PD-1 inhibitors. However, it is worth noting that this synergistic effect is achieved by affecting the immune system (no similar synergistic effect was observed in immunodeficient mice).
Furthermore, through a series of experiments, including single-cell RNA sequencing, the researchers found that PTDSS1 deficiency enhances the efficacy of PD-1 inhibitors because it significantly enhances tumor cell responsiveness to IFN-γ (e.g., increased MHC-I expression), thereby increasing tumor cell immunogenicity and making them more susceptible to recognition and elimination by CD8+ T cells. In addition, PTDSS1 deficiency also improves the tumor microenvironment (TME), increasing the number of tumor-infiltrating CD8+ T cells and the frequency of iNOS-positive myeloid cells, the latter of which is associated with a better anti-tumor immune response.
Figure 1. Loss of Ptdss1 in tumor cells increased the inflammatory potential of myeloid cells. (Liu J, et al., 2025)
Finally, to confirm the clinical translational value of the PTDSS1 target, the researchers analyzed human cancer databases (such as TCGA) and published clinical trial data. The results showed that PTDSS1 is highly expressed in various cancers, including bladder cancer, breast cancer, and melanoma. Furthermore, in a cohort of melanoma patients receiving PD-1 inhibitors, high PTDSS1 expression was significantly associated with a poorer treatment response and shorter survival. This suggests that PTDSS1 may serve not only as a functional target but also as a biomarker for predicting the efficacy of PD-1 inhibitors.
Overall, this study found that PTDSS1 is a key gene influencing the efficacy of PD-1 inhibitors. Its loss not only enhances tumor cells' inherent sensitivity to IFN-γ and immunogenicity but also synergistically enhances anti-PD-1 efficacy by remodeling the TME (specifically, inducing iNOS-positive myeloid cells). Furthermore, these results provide a theoretical basis for the development of future combination immunotherapy strategies using PTDSS1 inhibitors with PD-1 inhibitors.
Reference
Liu J, et al. Loss of PTDSS1 in tumor cells improves immunogenicity and response to anti–PD-1 therapy. Science Advances, 2025, 11(37): eadx8134.