Genetic Dysregulation of Immunologic and Oncogenic Signaling Pathways Associated with Tumor-intrinsic Immune Resistance: A Molecular Basis for Combination Targeted Therapy-Immunotherapy for Cancer

Abstract Since the turn of the century, advances in targeted therapy and immunotherapy have revolutionized the treatment of cancer. Although these approaches have far outperformed traditional therapies in various clinical settings, both remain plagued by mechanisms of innate and acquired resistance that limit therapeutic efficacy in many patients. With a focus on tumor-intrinsic resistance to immunotherapy, this review highlights our current understanding of the immunologic and oncogenic pathways whose genetic dysregulation in cancer cells enables immune escape. Emphasis is placed on genomic, epigenomic, transcriptomic, and proteomic aberrations that influence the activity of these pathways in the context of immune resistance. Specifically, the role of pathways that govern interferon signaling, antigen processing and presentation, and immunologic cell death as determinants of tumor immune susceptibility are discussed. Likewise, mechanisms of tumor immune resistance mediated by dysregulated RAS-MAPK, WNT, PI3K-AKT-mTOR, and cell cycle pathways are described. Finally, this review brings attention to the ways in which genetic dysregulation of these immunologic and oncogenic signaling pathways are informing the design of targeted interventions to restore immune susceptibility of cancer cells and enhance immunotherapeutic efficacy through combination targeted therapy-immunotherapy regimens that overcome the resistance mechanisms known to limit the success of monotherapies.