Dynamic Time-Resolved Remodeling of the Immune Microenvironment After Resistance to BRAF/MEK Inhibitors in Melanoma: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies

Targeted inhibition of the MAPK pathway with BRAF and MEK inhibitors (BRAFi/MEKi) produces rapid tumor regressions in BRAF V600-mutant melanoma, yet most patients ultimately develop acquired resistance. Resistance is not solely a tumor-cell-intrinsic phenomenon; it is accompanied by time-dependent remodeling of the tumor immune microenvironment (TIME) that can shape sensitivity to immune checkpoint inhibitors (ICIs) and inform rational combination or sequencing strategies. Early during MAPK inhibition, melanomas often display increased melanoma antigen expression and enhanced CD8+ T-cell infiltration, along with reduced immunosuppressive cytokines, suggesting a transient “immune-permissive” window. However, the same period can show induction of PD-L1 and T-cell exhaustion markers, foreshadowing adaptive immune resistance. At progression, immune-favorable features may diminish and immune evasion mechanisms, such as impaired antigen presentation and MHC-I downregulation, can become prominent and associate with resistance to immunotherapy. Here we review the temporal dynamics of TIME under MAPK inhibition, mechanistic links between resistance programs and immune remodeling, including signaling adaptation, focal adhesion/FAK signaling, dendritic cell dysfunction, antigen-presentation defects, and lymphatic/perilymphatic adipose remodeling, and practical biomarker opportunities across baseline, on-treatment, and progression timepoints. We also summarize emerging therapeutic strategies for post-resistance disease, including optimized ICI combinations, triple therapy concepts, and novel approaches such as combining FAK inhibition with RAF-MEK “clamp” therapy. Finally, we highlight key gaps and propose a framework for longitudinal sampling, standardized multi-omics integration, and TIME-informed trial design. The key distinguishing feature of this review is its time-resolved perspective on TIME remodeling, which links baseline immune contexture, early treatment-induced immune permissiveness, and the immune-evasive state that emerges during acquired resistance.