Cancer immunotherapy has long been proposed as a powerful approach to curing tumors, based on the natural function of the immune system in protecting its host with specificity, thus holding the potential for developing long-term memory that prevents tumor recurrence. However, the immunosuppressive feature of the tumor microenvironment prevents the patients' own immune system from functioning normally in the fight against cancer. As one of the most potent cancer immunotherapies, immunostimulatory cytokines have been shown to elicit anti-tumor immune responses in preclinical studies, but their clinical application is limited by severe immune-related adverse events upon systemic administration. None of the current delivery strategies can fully address issues of toxicities and sustainably supply cytokines over the course of a few days without compromising cytokines' structural integrity. Herein, we have developed a novel formulation to anchor potent cytokine molecules to the surface of large-sized particles (1 µm) for local cancer treatment. The cytokines are confined in tumors and have minimal systemic exposure over a few days following intratumoral injection, thereby eliciting anti-tumor immunity while avoiding the systemic toxicities caused by the circulating cytokines. Such particle-anchored cytokines can be synergistic with other immunotherapies, including immune checkpoint blockade antibodies and tumor antigens, to safely promote tumor regressions in various syngeneic tumor models and genetically engineered murine tumor models. / Doctor of Philosophy / Cancer immunotherapy is a promising method to treat cancer by harnessing the power of the body's immune system, which naturally fights off diseases and can remember and prevent diseases from returning. Unfortunately, cancers create a hostile environment that weakens the immune system's ability to combat the disease effectively. Among the treatments explored, immunostimulatory cytokines (unique proteins that boost the immune system) have shown great promise in laboratory studies for their ability to fight cancer. However, when these proteins are administered to patients, they can cause severe side effects due to their systemic dissemination throughout the body. Herein, by attaching the potent cytokines to large-sized particles (1 µm), and injecting them directly into the tumor, their cancer-fighting abilities are focused precisely where they are most needed. This targeted delivery minimizes the cytokines' presence in the rest of the body, dramatically reducing the risk of side effects associated with their systemic dissemination. This method not only shows promise on its own but also enhances the effectiveness of other cancer treatments. Our findings suggest a new, safer way to encourage the body's defense system to fight cancer more effectively.