Evaluation of NTRK3 mutation and a mutation-based gene set as biomarkers for immunotherapy outcomes in multiple cancers

Introduction: Immune checkpoint blockade (ICB) biomarkers like PD-L1 and TMB have limited utility. This study explores NTRK3 mutation as a novel ICB outcome biomarker and establishes a mutation-based gene set to optimize treatment decisions across cancers. Methods We analyzed immune landscapes of NTRK3 mutations using multi-omics data from TCGA pan-cancer cohorts (discovery cohort, n = 642; independent validation cohort, n = 1572) and our own cohort (n = 57). Key ICB outcomes (ORR, DCB, PFS, OS) were compared between NTRK3-mutated (NTRK3-Mut) and wild-type tumors. A mutation-based gene set containing NTRK3 was assessed via survival and clinical benefit analyses across multiple ICB-treated cohorts. Results NTRK3-Mut tumors in the discovery cohort showed significantly higher ORR (50.0% vs. 30.1%, P = 0.008) and DCB (60.9% vs. 42.6%, P = 0.020), improved PFS (HR = 0.65, P = 0.024), and a trend toward better OS (HR = 0.65, P = 0.086). These findings were validated in the independent and our own cohorts. Immune landscape analysis revealed NTRK3-Mut tumors had enhanced immunogenicity and a pro-inflammatory microenvironment versus NTRK3-Wild tumors. Additionally, the mutation-based gene set showed predictive performance comparable to TMB for identifying longer survival and higher DCB across cohorts. Conclusion NTRK3 mutation is a promising ICB biomarker. The gene set offers a practical tool to guide ICB decisions, refining immunotherapy biomarkers for better outcomes.