The Role of Alternative Splicing in Lung Cancer: Mechanisms, Regulators, and Therapeutic Implications

Lung cancer is characterized by profound molecular and clinical heterogeneity and remains the leading cause of cancer-related mortality worldwide. Its initiation and progression are shaped by complex genetic and epigenetic alterations that perturb key biological processes, including cell proliferation, apoptosis, metabolic reprogramming, invasion, metastasis, and immune evasion. Increasing evidence indicates that dysregulated alternative splicing (AS) represents a critical post-transcriptional regulatory mechanism involved in lung cancer pathogenesis. Although AS abnormalities are not the sole drivers of tumorigenesis, they contribute to malignant transformation, tumor progression, therapeutic resistance, and phenotypic plasticity, providing opportunities for biomarker development and therapeutic targeting. This review summarizes the multifaceted roles of AS in lung cancer biology, highlighting its contributions to tumor evolution, metastatic dissemination, and treatment resistance. Furthermore, subtype-specific AS landscapes between major lung cancer subtypes are discussed to elucidate their distinct molecular mechanisms and therapeutic implications. Representative AS-generated isoforms, including cluster of differentiation 44 variants (CD44v), are further discussed as examples of how aberrant splicing events regulate cancer stemness, tumor progression, and therapeutic responses. The regulatory mechanisms underlying CD44v generation, including upstream splicing factors and downstream signaling pathways, are also summarized. Collectively, this review highlights the emerging role of aberrant AS regulation in lung cancer and emphasizes its potential implications for biomarker discovery and precision therapeutic strategies targeting splicing dysregulation.