Cutaneous melanoma is a lethal form of skin cancer and is the 10th most common cause of cancer-related death in Australia. The recent development of both targeted therapies (TT), and immune checkpoint inhibitors (ICIs), have revolutionized the treatment of advanced-stage melanoma and improved the outcomes of patients with this malignancy. However, both therapies have their limitations. TT is associated with very high initial response rates that are typically short-lived, while in contrast ICIs provide more durable responses but have lower initial response rates. Hence, it has been proposed that sequencing ICIs with TT would lead to a higher frequency of durable responses. However, there are many unanswered questions regarding the choice of immunotherapy, the best sequencing strategy, and the mechanism leading to this synergy. To address these questions, we have optimized a syngeneic mouse melanoma model, YUMMER1.7-PV1 that is sensitive to both TT and ICIs. Importantly, this model recapitulates the known three therapeutic response phases of targeted therapies and immunotherapies: initial response, followed by drug tolerance, and then resistance. Investigation of the tumor immune microenvironment (TIME) at these three drug-induced phases, demonstrates that the immune suppressive microenvironment present during the acquired resistant phase is primed at the drug tolerance phase. Utilizing this model we have explored the time-dependent therapy-induced changes in both tumor cells and the TIME during various TT and ICI sequencing strategies. This information will determine the optimal sequencing strategy of targeted therapy and immunotherapy that will deliver better outcomes for melanoma patients.