Targeted therapies (TT-BRAFi/MEKi) have significantly advanced melanoma treatment, but therapy-induced plasticity remains a key driver of resistance. We utilized a syngeneic mouse-melanoma model that recapitulates this plasticity by replicating the three distinct therapeutic response phases of TT - initial tumour regression, drug tolerance, and resistance marked by transcriptional phenotypes previously described in patient-derived xenograft (PDX) models. Our investigation of the tumour immune microenvironment (TIME) revealed that the immune-suppressive microenvironment characteristic of the resistant phase is primed during the drug tolerance phase, a crucial window where melanoma cells exhibit heightened plasticity. To further understand the tumour-immune interactions driving this process, we performed single-cell RNA sequencing. This analysis identified distinct tumour cell clones, including neural crest stem cells (NCSCs), that actively remodel immune cell infiltration and function during the tolerance phase, ultimately fostering an immune-suppressive microenvironment. Importantly, we found that knocking out a key immunosuppressive cytokine inhibits the recruitment of regulatory immune cells, thereby mitigating the shift towards resistance by enhancing the anti-tumour immune response. Our findings highlight the tolerance phase as a critical period of therapy-induced plasticity, where immune evasion is established. Targeting NCSC-mediated plasticity, particularly the driven immunosuppressive pathways, presents a therapeutic opportunity to prevent resistance and improve treatment efficacy for melanoma patients.