Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review)

Abstract

Colorectal cancer (CRC) is a leading health issue and treatments to eradicate it, such as conventional chemotherapy, are non‑selective and come with a number of complications. The present review focuses on the relatively new area of precision oncolytic viral therapy (OVT), with genetic targeting and immune modifications that offer a new future for CRC treatment. In the present review, an overview of the selection factors that are considered optimal for an oncolytic virus, mechanisms of oncolysis and immunomodulation applied to the OVT, as well as new strategies to improve the efficacy of this method are described. Additionally, cause‑and‑effect relationships are examined for OVT efficacy, mediated by the tumor microenvironment, and directions for genetic manipulation of viral specificity are explored. The possibility of synergy between OVT and immune checkpoint inhibitors and other treatment approaches are demonstrated. Incorporating the details of the present review, biomarker‑guided combination therapies in precision OVT for individualized CRC care, significant issues and future trends in this required area of medicine are highlighted. Increasingly, OVT is leaving the experimental stage and may become routine practice; it provides a new perspective on overcoming CRC and highlights the importance of further research and clinical work.

Keywords: biomarkers; colorectal cancer; immune modulation; oncolytic viral therapy; personalized treatment; precision medicine.

Figure 1

Graphical abstract. This graphical abstract summarizes the role of OVT in CRC treatment, highlighting key challenges such as immune evasion, metastasis and drug resistance, and showcasing strategies such as CRISPR/Cas9 modifications, tumor-selective promoters and checkpoint inhibitors to enhance therapeutic efficacy. The outcomes illustrate OVT's ability to induce tumor cell lysis, release TAAs and stimulate antitumor immunity via CTLs, ultimately improving patient outcomes. This figure was created using BioRender (BioRender Inc.). CRC, colorectal cancer; OVT, oncolytic virus therapy; TAAs, tumor-associated antigens; CTLs, cytotoxic T lymphocytes; CRISPR, clustered regularly interspaced short palindromic repeats; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.

Figure 2

Strategies for engineering OVs for CRC therapy. This figure outlines the key steps in developing OVs for CRC therapy. It begins with selecting a suitable viral vector, such as adenovirus, followed by genetic modifications using tools such as CRISPR/Cas9 to enhance tumor specificity. Tumor-selective promoters (including telomerase-driven promoters) ensure targeted gene expression, while viral capsid modifications improve receptor targeting and reduce off-target effects. The integration of immune-stimulatory genes, such as IL-12 or CXCL11, boosts antitumor immunity. Finally, the figure highlights the importance of rigorous preclinical testing and validation through in vitro and in vivo studies as well as clinical trials to confirm safety and efficacy. These steps collectively illustrate the engineering and optimization process of OVs for CRC treatment. The material for this figure has been adapted from references (29-31,67,230-237). This figure was created using BioRender (BioRender Inc.). CRC, colorectal cancer; OV, oncolytic virus; CRISPR/Cas9, clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9; IL-12, interleukin-12; CXCL11, C-X-C motif chemokine ligand 11.

Figure 3

Synergistic mechanism of OV therapy and ICIs in CRC treatment. OVs are antitumor agents used in CRC treatment that infect and destroy CRC tumor cells through oncolysis and release TAAs, DAMPs and PAMPs. These molecules activate antigen-presenting cells, including dendritic cells, to identify and present TAAs to CTLs. CTL activation results in their subsequent recruitment to the tumor stroma and the identification and destruction of target tumor cells. The ICIs, which include anti-CTLA-4 and anti-PD-1/PD-L1, amplify the antitumor immune response by checkpoint blockade. Anti-CTLA-4 treatment and anti-PD-L1 therapy/reformatory strengthen T-cells, while anti-PD-1/PD-L1 therapy counterbalances the immunosuppressive tumor microenvironment that causes immune tolerance/escape. The integrated use of OVs and ICIs results in enhanced immune response and persistent tumor elimination, thus improving the therapeutic results. This figure was created using BioRender (BioRender Inc.). CRC, colorectal cancer; OV, oncolytic virus; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; ICIs, immune checkpoint inhibitors; TAAs, tumor-associated antigens; CTLs, cytotoxic T lymphocytes; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TCR, T cell receptor.

Figure 4

Comparison of systemic and intratumoral OV delivery methods for CRC. This figure illustrates the comparison between systemic and intratumoral delivery methods for OV therapy in CRC, highlighting their respective benefits, challenges and optimization strategies. Systemic delivery involves administering viruses through the bloodstream, enabling broad distribution and convenience but facing limitations such as limited penetration and potential systemic toxicities. By contrast, intratumoral delivery entails direct injection into the tumor, offering high local viral concentration and bypassing physical barriers, though it is technically complex and mostly limited to primary tumors. To enhance efficacy, nanoparticle encapsulation techniques protect viruses from degradation, extend circulation time and improve targeting by modifying the surface with tumor-specific ligands. Additionally, engineered vesicles, such as antibody-displayed extracellular vesicles, can deliver viruses specifically to tumor cells, increasing treatment specificity through targeted binding to upregulated receptors on cancer cells. These optimizations aim to improve specificity, immune response and therapeutic efficiency in CRC treatment. This figure was created using BioRender (BioRender Inc.). CRC, colorectal cancer; OV, oncolytic virus.