The emergence of therapeutic resistance remains a significant challenge in the treatment of cutaneous melanoma using targeted therapies (TT) such as BRAF and MEK inhibitors (BRAFi/MEKi). A recent ground-breaking clinical trial, DREAMseq, has shed light on an intriguing phenomenon whereby patients who develop resistance to TT also exhibit cross-resistance to the immune checkpoint inhibitors (ICI), anti-PD-1, and anti-CTLA-4 antibodies. This resistance is attributed to the reactivation of the mitogen-activated protein kinase (MAPK) pathway, which occurs in ~70% of patients and results in the establishment of an immune-suppressive microenvironment. However, a distinct subset of patients who have developed resistance to TT demonstrate responsiveness to second-line immunotherapy. To elucidate underlying mechanisms behind TT-induced cross-resistance, we have developed an innovative mouse melanoma model that is intrinsically resistant to BRAFi/MEKi but these inhibitors still induce an anti-tumor immune response. Notably, this model retains sensitivity to immune checkpoint inhibitors. An in-depth analysis of the tumor immune microenvironment (TIME) has revealed an upregulation of CD8+ T effector cells that critically contribute to controlling acquired resistant tumor cells. Additionally, we have discovered an upregulation of the epidermal growth factor receptor (EGFR) in TT-resistant melanoma, potentially serving as a biomarker to identify patients who may respond favorably to immune checkpoint inhibitors following progression on BRAF/MEK targeted therapy. These findings provide valuable insights into the interplay between TT resistance, immune response modulation, and biomarker-driven patient stratification in the context of melanoma treatment.