Unraveling the FGFR–RNA splicing axis: Mechanisms, oncogenic crosstalks and innovations for therapeutic purpose

Fibroblast growth factor receptor (FGFR) signaling is a pivotal regulator of tumor progression, driving cell proliferation, survival, metastasis, and therapeutic resistance across diverse cancer types. RNA alternative splicing profoundly shapes FGFR isoform diversity, endowing tumors with heterogeneity and adaptability to targeted interventions. While significant progress has been made in identifying splicing regulators that govern FGFR pre-mRNA processing, the extracellular cues influencing this process and the reciprocal impact of FGFR signaling pathway on global splicing networks remain underexplored. This review provides a comprehensive overview of the bidirectional interplay linking FGFR signaling and RNA splicing in cancer. Mechanistically, we first detail how <i>FGFR</i> mutations, epigenetic modifications, and crosstalks with oncogenic pathways reprogram splicing to generate tumor-specific FGFR splice variants. We then systematically classify distinct FGFR isoforms and delineate how they contribute to main cancer hallmarks, underscoring the central role of the FGFR-splicing axis in driving tumor plasticity, heterogeneity and adaptive progression. Conversely, we also examine how FGFR signaling modulates RNA splicing programs beyond FGFR itself, reshaping global splicing events that contribute to tumorigenesis, an emerging and still largely unexplored area of cancer biology. From therapeutic perspective, we highlight emerging strategies targeting the axis. Notably, FGFR splicing isoform-directed radiopharmaceuticals hold great promise for patient stratification and biomarker-directed theranostics, providing a precise approach to identify aggressive tumors and guide tailored interventions. As well, complementary approaches, including CRISPR/Cas9-based splicing modulation and long non-coding RNAs-targeted therapies, further expand the toolbox for isoform-specific intervention. Moreover, integrating splicing modulators with FGFR TKIs may overcome drug resistance. Understanding the intricate interplay between FGFR signaling and RNA splicing will not only advance biomarker-guided therapeutic development but also provide a novel framework to counteract tumor adaptability, ultimately improving outcomes in FGFR-driven malignancies.