Genome-Wide CRISPR Screen Identifies a microRNA Orchestrating Pleiotropic Resistance to Targeted Therapy and T Cell Immunity in Melanoma

  • Adv Sci (Weinh). 2026 May 26:e15158. doi: 10.1002/advs.202515158.
Zhao Wang  1  2 ,  Haotian Liu  3 ,  Xueqi Wang  4 ,  Jianjin Teng  4 ,  Zihan Zheng  1 ,  Jingya Zhang  5 ,  Wanyi Xiao  3 ,  Qian Liang  1  2  6 ,  Jiaxin Li  2 ,  Xiaomeng Jia  2 ,  Xin Feng  2 ,  Hongzhang Cui  2 ,  Menghan Luo  4 ,  Tielong Yang  3 ,  Liuxing Wu  4 ,  Ke Zhao  1 ,  Weilong Yang  5 ,  Mulin Jun Li  1  5 ,  Dandan Huang  1 ,  Jilong Yang  3
Affiliations
  • 1. Department of Pharmacology, State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
  • 2. Oujiang Laboratory, Wenzhou Medical University, Wenzhou, China.
  • 3. Department of Bone and Soft Tissue Tumor, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, National Clinical Research Center for Cancer, Tianjin, China.
  • 4. Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 5. Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
  • 6. Scientific Research Center, Wenzhou Medical University, Wenzhou, China.
PMID: 42189126 DOI: 10.1002/advs.202515158
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.

Keywords
CRISPR screen; T cell immunity; THBS1–CD47 axis; hippo signaling; melanoma; miR‐18a; targeted therapy resistance.
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