Signal sequence receptor subunit 3: A novel indicator of immunosuppressive tumor microenvironment and clinical benefits from immunotherapy

Background: Signal sequence receptor subunit 3 (SSR3), a translocation-associated protein complex, plays a vital role in various diseases. However, its involvement in human cancers remains unclear.Methods: We conducted a comprehensive analysis by integrating data from multiple sources, including the Cancer Genome Atlas, Cancer Cell Lineage Encyclopedia, Genotype Tissue Expression, Human Protein Atlas, cBioPortal, TIMER, and ImmuCellAI. Additionally, we incorporated data from a clinical trial, two immunotherapy cohorts, and in vitro experiments to investigate SSR3's impact on cancer prognosis and immune response.Results: Our findings revealed a significant correlation between elevated SSR3 expression and unfavorable prognosis across various cancer types. Amplification is the most common genetic alteration in SSR3. Furthermore, functional enrichment analysis highlighted SSR3's regulatory role in promoting proliferation. In addition, SSR3 also serves as a pivotal mediator bridging the innate and adaptive immune systems and several related signaling pathways. Moreover, the correlation of SSR3 expression with tumor mutation burden in five cancer types, as well as with microsatellite instability in nine cancer types, suggests the potential of SSR3 as a predictive marker for immunotherapy response. To validate this hypothesis, we examined data from patients who underwent immunotherapy treatment. Our analysis revealed that individuals with low SSR3 expression demonstrated higher response rates to immune checkpoint inhibitors and longer overall survival compared to those with high SSR3 expression.Conclusions: Our study identifies SSR3 as a potential oncogene in humans, implicated in both tumorigenesis and cancer immunity. Elevated SSR3 expression is indicative of an immunosuppressive tumor microenvironment. Therefore, SSR3 holds promise as a potential prognostic biomarker and a target for immunotherapy in cancer treatment.