ABSTRACT Acquired resistance to both targeted therapies and immunotherapies in cancer presents major clinical challenges, yet the molecular mechanisms underlying cross‐resistance remain poorly understood. We hypothesized that loss of specific microRNAs (miRNAs) could potentiate melanoma resistance to both targeted drugs and CD8 + T cell‐mediated cytotoxicity. Through genome‐wide miRNA CRISPR knockout screening integrated with cellular models, longitudinal clinical samples, and in vivo experiments, we identified miR‐18a as a pivotal upstream regulator of pleiotropic resistance in melanoma. We show that miR‐18a deficiency drives resistance through two distinct mechanisms: derepressing AJUBA‐regulated Hippo signaling during MAPK inhibition, and enhancing THBS1–CD47 interactions that impair the immunological synapse between tumor cells and CD8 + T cells. Furthermore, hnRNP A1 plays an essential role in modulating miR‐18a expression, thereby mediating cross‐resistance. These findings suggest that targeting non‐coding RNA vulnerabilities may represent a promising therapeutic strategy to overcome complex resistance mechanisms and improve clinical outcomes in melanoma.
Wang et al. (Tue,) studied this question.