Unravelling Cancer Immunity: Coagulation.Sig and BIRC2 as Predictive Immunotherapeutic Architects

ABSTRACT Immune checkpoint inhibitors (ICIs) represent a groundbreaking advancement in cancer therapy, substantially improving patient survival rates. Our comprehensive research reveals a significant positive correlation between coagulation scores and immune‐related gene expression across 30 diverse cancer types. Notably, tumours exhibiting high coagulation scores demonstrated enhanced infiltration of cytotoxic immune cells, including CD8 + T cells, natural killer (NK) cells, and macrophages. Leveraging the TCGA pan‐cancer database, we developed the Coagulation.Sig model, a sophisticated predictive framework utilising a coagulation‐related genes (CRGs) to forecast immunotherapy outcomes. Through rigorous analysis of ten ICI‐treated cohorts, we identified and validated seven critical CRGs: BIRC2, HMGB1, STAT2, IFNAR1, BID, SPATA2, IL33 and IFNG, which form the foundation of our predictive model. Functional analyses revealed that low‐risk tumours characterised by higher immune cell populations, particularly CD8 + T cells, demonstrated superior ICI responses. These tumours also exhibited increased mutation rates, elevated neoantigen loads, and greater TCR/BCR diversity. Conversely, high‐risk tumours displayed pronounced intratumor heterogeneity (ITH) and elevated NRF2 pathway activity, mechanisms strongly associated with immune evasion. Experimental validation highlighted BIRC2 as a promising therapeutic target. Targeted BIRC2 knockdown, when combined with anti‐PD‐1 therapy, significantly suppressed tumour growth, enhanced CD8 + T cell infiltration, and amplified IFN‐γ and TNF‐α secretion in tumour models. Our findings position the Coagulation.Sig model as a novel, comprehensive approach to personalised cancer treatment, with BIRC2 emerging as both a predictive biomarker and a potential therapeutic intervention point.