Abstract
BACKGROUND: The IFN-γ cytokine plays a dual role in anti-tumor immunity, enhancing immune defense against cancer cells while promoting tumor survival and progression. Its influence on prognosis and therapeutic responses across cancer types remains unclear. OBJECTIVE: This study aimed to perform a pan-cancer analysis of IFN-γ response genes to determine their prognostic significance and evaluate their impact on clinical outcomes and anti-PD1 immunotherapy responses. METHODS: Using multiple datasets, 46 IFN-γ response genes were identified as prognostic for disease-specific survival, and their expression was used to construct the IFN-γ Response Gene Network Signature (IFGRNS) score. The prognostic and therapeutic relevance of the IFGRNS score was assessed across cancer types, considering tumor pathology, genomic alterations, tumor mutation burden, and microenvironment. Single-cell transcriptomic analysis identified cellular contributors, and a murine pancreatic cancer (PAN02) model was used to validate findings with anti-PD1 therapy. RESULTS: The IFGRNS score emerged as a robust prognostic indicator of survival, with higher scores correlating with worse outcomes in most cancer types. The prognostic significance of the score was influenced by factors such as cancer type, tumor pathology, and the tumor microenvironment. Single-cell analysis revealed that myeloid cells, particularly the M2 macrophage subtype, demonstrated high levels of IFGRNS expression, which was associated with tumor progression. A negative correlation was observed between the IFGRNS score and outcomes to anti-PD1 immunotherapy in urologic cancers, where patients with higher scores showed worse prognosis and lower response rates to therapy. Experimental validation in the PAN02 murine model confirmed that anti-PD1 therapy significantly reduced tumor size and IFGRNS expression in M2 macrophages, supporting the clinical findings. CONCLUSIONS: The IFGRNS score is a novel prognostic indicator for survival and therapeutic responses in cancer. These findings underline the complexity of IFN-γ signaling and suggest potential applications for the IFGRNS score in cancer diagnosis, prognosis, and immunotherapy. Novelty & impact statements: IFN-γ response genes play a significant role in tumour biology, yet comprehensive analysis across various cancers is limited. This study identifies a novel prognostic biomarker, the IFGRNS score, which is elevated in myeloid lineage cells and correlates with survival across multiple cancers. The IFGRNS score is also associated with tumour pathology, immune microenvironment, and immunotherapy response, highlighting its diagnostic and therapeutic potential in cancer management. KEY POINTS: IFN-γ cytokine plays a dual role in cancer, aiding immune defense but also promoting tumor progression. A novel IFGRNS score, based on 46 IFN-γ response genes, was identified as a strong prognostic marker for survival across cancer types. Higher IFGRNS scores correlate with worse prognosis and reduced response to anti-PD1 immunotherapy, particularly in urologic cancers. M2 macrophages were identified as key contributors to high IFGRNS scores, associated with tumor progression. Findings were validated in a murine cancer model, highlighting the potential of the IFGRNS score for cancer prognosis and therapy guidance.