Silenced Gene PRSS33 Reactivates Antitumor Immunity in Myelodysplastic Syndromes

A gene silenced in myelodysplastic syndromes (MDS) may hold the key to reversing the immunosuppressive environment that lets the bone marrow disorder progress. In a study published in Cellular & Molecular Biology Letters, researchers identified PRSS33 as a tumor suppressor gene frequently switched off by promoter hypermethylation in MDS patients, and showed that restoring it triggers immunogenic cell death, a process that rallies antitumor immunity.

MDS are clonal hematopoietic disorders marked by ineffective hematopoiesis, cytopenias, and an immunosuppressive bone marrow microenvironment. Although immunogenic cell death (ICD) is considered therapeutically promising because it can activate antitumor immune responses, the role of endogenous ICD inducers in MDS pathogenesis and immune evasion had remained poorly understood. The team addressed this gap by integrating methylome and transcriptome analyses of MDS patient samples.

That integration pinpointed PRSS33 as a candidate tumor suppressor gene frequently silenced by promoter hypermethylation. Low expression of the gene correlated with poor survival in patients. When the researchers applied hypomethylating agents, PRSS33 expression was restored, confirming that the gene is under epigenetic regulation in these disorders.

Functionally, the restoration of PRSS33 suppressed proliferation, induced cell cycle arrest and apoptosis, and promoted myeloid differentiation in vitro. In animal models, PRSS33 restoration inhibited tumor growth. These results establish the gene as a multi-level suppressor of malignant hematopoietic cells rather than a marker of disease alone.

The mechanistic core of the study lies in endoplasmic reticulum stress. PRSS33 triggered ER stress, which set off a robust immunogenic cell death response characterized by three hallmark signals: exposure of calreticulin on the cell surface, release of ATP, and release of HMGB1.

These danger signals reshaped the immune landscape around the tumor cells. The ICD response enhanced macrophage phagocytosis, promoted polarization of macrophages toward the inflammatory M1 state, and stimulated dendritic cell maturation. Together, these effects convert a tumor cell’s death into an immune-activating event rather than a silent one.

To test the consequences of losing the gene, the researchers knocked down PRSS33 in NHD13 MDS mice. The loss aggravated cytopenias and erythroid dysplasia and fostered an immunosuppressive microenvironment, with expansion of myeloid-derived suppressor cells and loss of T cells. This genetic evidence directly links epigenetic silencing of PRSS33 to immune escape in vivo.

The team also explored therapeutic implications. Vaccination with PRSS33-overexpressing cells elicited immune-associated effects and altered in vitro responsiveness to BMS-1, a PD-1/PD-L1 pathway inhibitor. The authors note these findings support PRSS33 reactivation as a rational strategy to remodel the immunosuppressive microenvironment and enhance existing therapies for MDS.

The study is published as open access research and, at the time of reporting, is being shared early as a peer-reviewed, accepted version of record that remains subject to further edits. As with all pre-final publications, the findings await the finalized version, but the evidence presented positions PRSS33 at the intersection of epigenetic silencing and immune evasion in MDS, supporting PRSS33 reactivation as a strategy to remodel the immunosuppressive microenvironment and enhance existing therapies for MDS.

Subject of Research: Epigenetic silencing of PRSS33 and its reactivation as an immunogenic cell death inducer in myelodysplastic syndromes

Article Title: PRSS33 reactivation triggers immunogenic cell death to overcome immunosuppression in myelodysplastic syndromes

Article References: Luo, J., Liu, Y., Yin, J., Luo, J., Pan, S., He, X., Hou, Y., & Liu, L. (2026). PRSS33 reactivation triggers immunogenic cell death to overcome immunosuppression in myelodysplastic syndromes. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01005-8

Image Credits: AI Generated

DOI: 10.1186/s11658-026-01005-8

Keywords: PRSS33, myelodysplastic syndromes, immunogenic cell death, promoter hypermethylation, hypomethylating agents, endoplasmic reticulum stress, calreticulin, HMGB1, macrophage phagocytosis, tumor suppressor, immune evasion, NHD13 mouse model