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Updated: Jan 7, 2026

Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Alternative Splicing-Mediated Resistance to Antibody-Based Therapies: Mechanisms and Emerging Therapeutic Strategies

Sanga Choi1, Jieun Kang1, Jung-Hyun Kim1

  • 1Research Institute, National Cancer Center, 323 Ilsan-ro, Goyang-si 10408, Gyeonggi-do, Republic of Korea.

International Journal of Molecular Sciences
|December 30, 2025
PubMed

Insights

Alternative splicing (AS) drives cancer immune escape by altering tumor surface antigens, limiting antibody therapies. Strategies correcting AS offer new ways to enhance cancer treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Antibody therapies targeting tumor surface markers are crucial in cancer treatment.
  • Tumor escape mechanisms like antigen loss and heterogeneous expression limit therapeutic efficacy.
  • RNA alternative splicing (AS) is an emerging post-transcriptional driver of antigenic diversity and immune evasion.

Purpose of the Study:

  • To review how alternative splicing (AS) generates diverse protein isoforms.
  • To outline the role of AS in resistance to antibody-based cancer therapies.
  • To discuss emerging therapeutic strategies targeting AS for improved cancer treatment.

Main Methods:

  • Literature review of studies on RNA alternative splicing in cancer.
  • Analysis of AS-generated isoforms affecting key therapeutic targets (e.g., CD19, EGFR, PD-1/PD-L1).
  • Examination of splicing regulators' aberrant activity and its consequences.

Main Results:

  • AS remodels surface antigen structure and function, promoting resistance to monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibitors.
  • Aberrant splicing leads to altered receptor signaling or secretion of soluble decoy isoforms that evade immune recognition.
  • Specific examples include altered isoforms of CD19, CD20, CD22, EGFR, HER2, VEGF, and PD-1/PD-L1.

Conclusions:

  • Alternative splicing represents a significant layer of resistance in antibody-based cancer therapies.
  • Understanding splicing-driven antigenic plasticity is key to developing next-generation therapies.
  • RNA-informed strategies, including splicing correction and isoform-selective designs, hold promise for enhancing durable clinical responses.
Keywords:
alternative splicingantibody therapy resistanceimmune checkpoint blockadeisoform diversityprecision oncologysplicing factors

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