Precise diagnosis and treatment of tumors currently still face considerable challenges due to the development of highly degreed heterogeneity in the dynamic evolution of tumors. With the rapid development of genomics, personalized diagnosis and treatment using specific genes may be a robust strategy to break through the bottleneck of traditional tumor treatment. Nevertheless, efficient in vivo gene delivery has been frequently hampered by the inherent defects of vectors and various biological barriers. Encouragingly, spherical nucleic acids (SNAs) with good modularity and programmability are excellent candidates capable of addressing traditional gene transfer-associated issues, which enables SNAs a precision nanoplatform with great potential for diverse biomedical applications. In this regard, there have been detailed reviews of SNA in drug delivery, gene regulation, and dermatology treatment. Still, to the best of our knowledge, there is no published systematic review summarizing the use of SNAs in oncology precision medicine and immunotherapy, which are considered new guidelines for oncology treatment. To this end, we summarized the notable advances in SNAs-based precision therapy and immunotherapy for tumors following a classification standard of different types of precise spatiotemporal control on active species by SNAs. Specifically, we focus on the structural diversity and programmability of SNAs. Finally, the challenges and possible solutions were discussed in the concluding remarks. This review will promote the rational design and development of SNAs for tumor-precise medicine and immunotherapy.