Alternative Splicing in Lung Adenocarcinoma: Mechanisms and Immunotherapeutic Perspectives
In the complex molecular landscape of lung adenocarcinoma, alternative splicing has emerged as both a driver of disease progression and a promising therapeutic target. This dynamic process—where a single gene can yield multiple protein isoforms through selective exon inclusion or exclusion—expands proteomic diversity but, when dysregulated, can also give rise to aberrant oncogenic variants. As researchers delve deeper into these splicing events, a new era of personalized oncology is beginning to take shape.
Lung adenocarcinoma, the most prevalent subtype of non-small cell lung cancer (NSCLC), accounts for a significant proportion of cancer-related deaths worldwide. While genetic mutations such as EGFR, KRAS, and ALK have long guided targeted therapy development, attention is increasingly turning to post-transcriptional regulation—specifically, how alternative splicing rewires cellular signaling, immune interactions, and tumor microenvironment dynamics.
Recent studies underscore the integral role of alternative splicing in facilitating tumorigenesis. Splicing errors can produce gain-of-function isoforms that bypass regulatory checkpoints or generate loss-of-function variants that impair tumor suppressor genes. For instance, alterations in splicing factors like SRSF1 or mutations in core spliceosomal components can tilt the cellular balance toward malignancy, fostering unchecked proliferation, resistance to apoptosis, and metastatic potential.
The advent of multi-omics profiling has catalyzed progress in this field. By integrating genomic, transcriptomic, and proteomic data, researchers are now mapping splicing landscapes with unprecedented precision. These approaches have unveiled cancer-specific splicing signatures that not only distinguish malignant from healthy tissue but also correlate with clinical outcomes and therapeutic responsiveness. Notably, certain splice variants have been linked to immune escape mechanisms, revealing how tumors may modify their surface antigens or suppress immune cell infiltration through altered isoform expression.
This molecular granularity is beginning to translate into clinical innovation. Liquid biopsies, enriched by RNA-seq and splicing-aware bioinformatics pipelines, are being explored as tools for non-invasive detection of tumor-specific splice variants. Meanwhile, splicing-modulating drugs—some targeting spliceosome machinery directly, others influencing exon selection—are entering early-phase trials.
Perhaps most compelling is the immunotherapeutic potential of splicing-derived neoantigens. Unlike canonical tumor antigens, these peptides are generated uniquely by cancer-associated splice variants, making them highly specific and less susceptible to immune tolerance. Preclinical models have demonstrated that chimeric antigen receptor (CAR) T cells engineered to recognize such neoantigens can selectively target tumor cells while sparing healthy tissue.
Platforms like Frontiers in Immunology and MDPI have spotlighted ongoing efforts to catalog these neoantigens and develop robust pipelines for their validation. The feasibility of designing personalized CAR T therapies, or splicing-targeted vaccines, hinges on the ability to accurately identify which splice variants are both tumor-specific and immunogenic—an area where bioinformatics and immunopeptidomics converge.
Yet translating these molecular insights into clinical therapies remains a work in progress. Technical hurdles in splicing variant detection, tumor heterogeneity, and immune editing continue to challenge implementation. Moreover, understanding how alternative splicing interacts with the broader tumor microenvironment—particularly with immune checkpoints and cytokine signaling—will be essential to optimizing combinatorial treatment strategies.
Still, the trajectory is clear: alternative splicing is no longer a peripheral curiosity in cancer biology but a central axis of both tumor behavior and therapeutic opportunity. As research deepens, it’s conceivable that splicing signatures will not only guide diagnostics and prognostics but also become actionable targets in immuno-oncology. The integration of multi-omics data, computational modeling, and translational science is bringing this vision closer to reality.
In the coming years, the convergence of RNA biology and cancer immunotherapy may redefine how clinicians approach lung adenocarcinoma. By harnessing the specificity of splicing-derived neoantigens and the precision of individualized therapy, a new frontier of targeted, immune-based interventions may finally be within reach.
