A new computational tool, SNAF (Splicing Neo Antigen Finder), was developed to identify and prioritize splicing-derived neoantigens that could serve as targets for cancer immunotherapy. SNAF integrates deep-learning and probabilistic algorithms to predict immunogenic splicing neoantigens (SNAF-T), full-length transmembrane tumor-specific isoforms (SNAF-B), and regulators of mis-splicing (RNA-SPRINT). The tool was validated using mass spectrometry, immunopeptidomics, and T-cell reactivity assays, showing that splicing neoantigens are frequently shared among melanoma patients and can predict survival and response to immunotherapy. Shared splicing neoantigens were found in up to 90% of melanoma patients, correlated with overall survival in multiple cancer cohorts, and were characterized by distinct cells of origin and amino acid preferences. SNAF-B identified a new class of tumor-specific extracellular neo-epitopes, ExNeoEpitopes, which were validated using long-read isoform sequencing and in vitro transmembrane localization assays. These findings suggest that splicing neoantigens represent an untapped reservoir of shared targets for targeted cancer immunotherapy. SNAF's ability to identify splicing neoantigens with high accuracy and specificity could lead to new therapeutic strategies for heterogeneous cancers. The study also highlights the importance of splicing factor dysregulation in splicing neoantigen burden and the potential of splicing neoantigens as targets for immunotherapy. The results demonstrate that splicing neoantigens can be used to predict patient outcomes and guide personalized cancer treatment. SNAF provides a systematic approach to identify splicing neoantigens that can be exploited by current immunotherapy strategies. The tool's interactive web applications allow for the visualization and prioritization of predicted neoantigens, facilitating further research and development of targeted immunotherapies. The study underscores the potential of splicing neoantigens as shared targets for cancer immunotherapy and highlights the need for further research to fully understand their role in cancer treatment.A new computational tool, SNAF (Splicing Neo Antigen Finder), was developed to identify and prioritize splicing-derived neoantigens that could serve as targets for cancer immunotherapy. SNAF integrates deep-learning and probabilistic algorithms to predict immunogenic splicing neoantigens (SNAF-T), full-length transmembrane tumor-specific isoforms (SNAF-B), and regulators of mis-splicing (RNA-SPRINT). The tool was validated using mass spectrometry, immunopeptidomics, and T-cell reactivity assays, showing that splicing neoantigens are frequently shared among melanoma patients and can predict survival and response to immunotherapy. Shared splicing neoantigens were found in up to 90% of melanoma patients, correlated with overall survival in multiple cancer cohorts, and were characterized by distinct cells of origin and amino acid preferences. SNAF-B identified a new class of tumor-specific extracellular neo-epitopes, ExNeoEpitopes, which were validated using long-read isoform sequencing and in vitro transmembrane localization assays. These findings suggest that splicing neoantigens represent an untapped reservoir of shared targets for targeted cancer immunotherapy. SNAF's ability to identify splicing neoantigens with high accuracy and specificity could lead to new therapeutic strategies for heterogeneous cancers. The study also highlights the importance of splicing factor dysregulation in splicing neoantigen burden and the potential of splicing neoantigens as targets for immunotherapy. The results demonstrate that splicing neoantigens can be used to predict patient outcomes and guide personalized cancer treatment. SNAF provides a systematic approach to identify splicing neoantigens that can be exploited by current immunotherapy strategies. The tool's interactive web applications allow for the visualization and prioritization of predicted neoantigens, facilitating further research and development of targeted immunotherapies. The study underscores the potential of splicing neoantigens as shared targets for cancer immunotherapy and highlights the need for further research to fully understand their role in cancer treatment.