The immunosuppressive tumor microenvironment (TME) plays a crucial role in the progression and treatment resistance of melanoma. Modulating the TME is thus a key strategy for enhancing therapeutic outcomes. Previousstudies have identified clonidine (CLD), an α2-adrenergic receptor agonist, as a promising agent that enhances T lymphocyte infiltration and reduces myeloid-derived suppressor cells within the TME, thereby promoting antitumor immune responses. In this study, we discovered that CLD reshaped the melanoma immune microenvironment, facilitating T-cell activation and exerting antitumor effects. However, the high doses of CLD required for effective TME modulation pose significant toxicity concerns, limiting its clinical applicability. To address this, we employed the controllable cavitation-on-a-chip (CCC) platform to formulate CLD-loaded liposomes and optimize their size. This approach aimed to enhance the precision and efficacy of drug delivery while reducing systemic side effects. Our results demonstrated that size-specific CLD liposomes, particularly those at 50 nm, significantly improved tumor growth inhibition and immune cell infiltration within the TME. Moreover, these optimized liposomes mitigate adverse effects associated with high-dose CLD treatment. This study indicates the potential of CCC-optimized CLD liposomes as a safer and more effective melanoma therapy, highlighting the critical interplay between liposome size control and therapeutic outcomes in cancer treatment.