The inherent limitations of conventional cancer treatments, including systemic toxicity, drug resistance, and insufficient tumor selectivity, have highlighted the need for the development of more effective therapeutic strategies. In this context, metal nanoparticles have emerged as multifunctional platforms with advanced therapeutic potential owing to their tunable physicochemical properties and versatile engineering capabilities. However, the lack of a systematic comparative understanding of the structure-function relationships among different classes of metal nanoparticles has hindered their rational design and clinical translation. This review provides a comparative analysis of major metal-based nanoplatforms, including gold, silver, iron oxide, and zinc oxide nanoparticles, from a design-oriented perspective. Particular emphasis is placed on the relationship between key physicochemical parameters, such as particle size, morphology, surface charge, composition, and surface functionalization, and their associated biological mechanisms, including reactive oxygen species (ROS) generation, apoptosis induction, localized hyperthermia, and targeted drug delivery. The findings indicate that the biological performance of metal nanoparticles is strongly governed by the dynamic interplay between their structural characteristics and the tumor microenvironment. Simultaneous optimization of physicochemical properties and targeting strategies can substantially improve the therapeutic index while minimizing adverse effects. Nevertheless, critical challenges, including long-term toxicity, biodistribution and bioaccumulation concerns, as well as barriers to clinical translation, remain significant obstacles. Addressing these challenges requires standardized safety evaluation frameworks and more reliable predictive models. Collectively, the insights presented in this review provide a foundation for the rational design of next-generation metal nanoparticles with enhanced therapeutic efficacy, improved selectivity, and optimized biosafety for future cancer treatment applications.