مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
MicroRNA-Guided Oncolytic Virotherapy Targeting Anoikis-Resistant Cancer Cells: A Novel Strategy for Selective Replication and Immune Activation
MicroRNA-Guided Oncolytic Virotherapy Targeting Anoikis-Resistant Cancer Cells: A Novel Strategy for Selective Replication and Immune Activation
Ehsan Kakavandi,1,*Mohammad Shayestehpour,2
1. Reference health laboratory, Deputy of Health, Isfahan University of Medical Sciences, Isfahan, Iran. 2. Department of Bacteriology and Virology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Introduction: Oncolytic viruses (OVs) are engineered or naturally occurring viruses that selectively infect and lyse cancer cells while sparing normal tissues. A major challenge in virotherapy is achieving tumor-specific replication without off-target toxicity. Recent reports suggest that microRNAs (miRNAs) could be harnessed to fine-tune OV tropism. It has been shown that by incorporating miRNA target sites into viral genomes, replication can be restricted to cells lacking specific tumor-suppressive miRNAs or overexpressing oncogenic ones. This strategy is aligned with our ongoing work on epitranscriptomic modifications and anoikis resistance in virus-associated cancers, where we explore how RNA-level regulation contributes to tumor progression.
Methods: This work synthesizes findings from peer-reviewed papers published between 2016 and 2025, focusing on miRNA-regulated replication of OVs in cancer models. Literature was retrieved from PubMed, Scopus, and Web of Science using keywords including “oncolytic virus,” “microRNA targeting,” “tumor selectivity,” “virotherapy,” “cancer tropism,” “anoikis resistance,” and “epitranscriptomic regulation.” Studies were selected based on experimental validation, novelty, and relevance to miRNA-guided viral engineering. Special attention was given to research involving miRNA-responsive elements in adenoviruses, herpesviruses, and reoviruses, as well as their impact on tumor microenvironment, transcriptomic dynamics, and immune modulation.
Results: It has been demonstrated that insertion of microRNA target sequences into oncolytic viral genomes can suppress replication in non-cancerous cells while permitting robust replication in tumor cells. For example, miR-122-targeted adenoviruses show reduced hepatotoxicity and enhanced selectivity for hepatocellular carcinoma by avoiding replication in hepatocytes where miR-122 is highly expressed. Similarly, miR-34a-responsive herpes simplex viruses preferentially replicate in p53-deficient tumors, exploiting the downregulation of miR-34a to bypass antiviral suppression and enhance viral gene expression. Reoviruses engineered with let-7 target sites avoid replication in normal tissues where let-7 is abundant, but thrive in let-7-deficient cancers, where derepression of viral transcripts leads to increased viral polymerase and capsid synthesis. These examples collectively have shed light on how miRNA dysregulation in cancer cells can be exploited to achieve selective viral replication. Notably, these miRNA-guided OVs showed preferential replication in detached, anoikis-resistant tumor cells, which often exhibit altered integrin signaling, upregulated PI3K/AKT pathways, and suppressed caspase-8 activity. In these cells, the lack of specific tumor-suppressive miRNAs such as miR-145 or miR-200c facilitates viral genome stability and translation, promoting efficient replication. These engineered viruses also induce immunogenic cell death characterized by calreticulin exposure, HMGB1 release, and ATP secretion, thereby enhancing antigen presentation and T-cell recruitment within the tumor microenvironment. Importantly, miRNA-guided OV replication may intersect with epitranscriptomic mechanisms described in our ongoing research, as RNA modifications such as N6-methyladenosine (m6A) and 5-methylcytosine (m5C) can alter miRNA biogenesis, AGO2 loading, and target recognition. These modifications influence the stability and accessibility of both viral and host transcripts, further refining viral tropism and efficiency of replication. These findings suggest that transcriptomic and epitranscriptomic alterations in anoikis-resistant cancer cells—such as differential expression of RNA-binding proteins (e.g., IGF2BP1, YTHDF1) and dysregulated miRNA processing enzymes (e.g., DROSHA, DICER)—may serve as prognostic biomarkers for OV responsiveness, offering a better targeted therapy.
Conclusion: MicroRNA-guided replication control offers a promising avenue for improving the safety and specificity of oncolytic virotherapy. By integrating tumor-specific miRNAs into viral design, researchers can achieve precise targeting of cancer cells while minimizing collateral damage. This dual-layered strategy—combining miRNA-guided selectivity with insights from RNA modifications—represents a novel therapeutic paradigm in virus-based oncology. Clinical translation of this approach will require validation in patient-derived xenograft models and integration with existing immunotherapy platforms. Ultimately, miRNA-guided oncolytic virotherapy—when combined with epitranscriptomic profiling—may enable precision oncology strategies tailored to the molecular vulnerabilities of metastatic and anoikis-resistant tumors. This emerging strategy holds potential for personalized cancer treatment and may redefine the therapeutic landscape of virus-based oncology.