The advancement of nanomedicine tailored to respond to localized energy inputs or the intricacies of the tumor microenvironment (TME) is pivotal in enhancing cancer therapy by improving efficacy while minimizing side effects. Polyoxometalates (POMs), a distinctive class of inorganic clusters, stand out as a reservoir of metallic therapeutic agents capable of not only responding to or modulating the TME but also harnessing various energy sources to induce potent antitumor effects. These multifaceted properties allow POMs to surpass traditional therapeutic approaches, offering a refined strategy for precision oncology. Notably, the unique physicochemical characteristics of POMs confer them with exceptional biological functionalities, establishing a compelling framework for the design of targeted anticancer therapies. The exploration and deployment of POMs in oncological treatments represent a burgeoning field with significant promise. This review provides a comprehensive overview of the applications of POMs across a spectrum of antitumor modalities, including chemotherapy, chemodynamic therapy, photothermal therapy, photodynamic therapy, radiotherapy, sonodynamic therapy, electrodynamic therapy, and immunotherapy. Furthermore, the potential for clinical translation of POM-based nanomedicine is critically examined, highlighting both the opportunities and challenges that lie ahead. This review underscores the transformative potential of POMs in the landscape of cancer therapeutics.