Melanoma Differentiation Trajectories Determine Sensitivity toward Pre-Existing CD8⁺ Tumor-Infiltrating Lymphocytes

The highly plastic nature of melanoma enables its transition among diverse cell states to survive hostile conditions. However, the interplay between specific tumor cell states and intratumoral T cells remains poorly defined. With MAPK inhibitor‒treated BRAF^V600-mutant tumors as models, we linked human melanoma state transition to CD8⁺ T cell responses. Repeatedly, we observed that isogenic melanoma cells could evolve along distinct differentiation trajectories on single BRAF inhibitor (BRAFi) treatment or dual BRAFi/MEKi treatment, resulting in BRAFi‒induced hyperdifferentiated and BRAFi/MEKi‒induced dedifferentiated resistant subtypes. Taking advantage of patient-derived autologous CD8⁺ tumor-infiltrating lymphocytes (TILs), we demonstrate that progressive melanoma cell state transition profoundly affects TIL function. Tumor cells along the hyperdifferentiation trajectory continuously gained sensitivity toward tumor-reactive CD8⁺ TILs, whereas those in the dedifferentiation trajectory acquired T cell resistance in part owing to the loss of differentiation antigens. Overall, our data reveal the tight connection of MAPKi‒induced temporary (drug-tolerant transition state) and stable (resistant state) phenotype alterations with T cell function and further broaden the current knowledge on melanoma plasticity in terms of sculpting local antitumor immune responses, with implications for guiding the optimal combination of targeted therapy and immunotherapy.