Dendritic cells (DCs) play a crucial role in the coordination of immune responses and have emerged as a potential target for cancer immunotherapy. However, existing DC-based immunotherapies face several clinical challenges, including suboptimal manipulation strategies, poor cross-presentation, and impaired migration. Besides, the complex tumor milieu drives DCs towards a tolerogenic state, leading to immune evasion and cancer progression. Hence, innovative engineering strategies emerging from a thorough understanding of the genetic and molecular aspects of the factors driving DCs to an immune-compromised status will benefit cancer immunotherapy. Taking advantage of the multiplexing potential of gene editing methods such as CRISPR/Cas9 and viral vectors will ensure multiple genome modifications in DCs that can result in higher migration, cross-presentation, and immune-activating cytokine production in a single manipulation step. Such precise DC modifications with high accuracy require the involvement of nanocarrier formulations with high surface functionalization and targeting potential. In this regard, our review provides a comprehensive summary of critical tumor-induced dysfunctions in DCs and promising genome engineering strategies, highlighting nanocarrier-based approaches to mitigate these challenges.