Abstract Genetic alterations in immune-related pathways are common hallmarks of cancer. However, to realize the full potential of immunotherapy, a comprehensive understanding of immune networks and how mutations impact network structure and functional output across cancer types is instrumental. Herein we systematically interrogated somatic mutations that could express neoantigens and alter immune responses in cancer patients compared to wild-type controls. To do so, we developed a network-based immunogenomics model (NIPPER) with scoring systems to prioritize critical genes and mutations eliciting differential HLA binding affinity and alternate responses to immunotherapy. These mutations are enriched in essential protein domains and often alter tumor infiltration by immune cells, affecting T cell receptor repertoire and B cell clonal expansion. Furthermore, we devised an interactome network propagation framework integrated with drug associated gene signatures to identify potential immunomodulatory drug candidates. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients, and serve as a resource for future functional studies and targeted therapeutics. Significance Cancer cells induce specific immune-related pathway perturbations by mutations, transcriptional dysregulation, and integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics.

Comprehensive and Integrated Genomic Characterization of Human Immunome in Cancer