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Oncolytic Influenza A Virus as an Emerging Therapeutic Modality for Pancreatic Cancer: A Narrative Review
Pudjiatmoko
Member of the Nanotechnology
Technical Committee, National Standardization Agency, Indonesia
Abstract
Pancreatic ductal adenocarcinoma
(PDAC) remains one of the most lethal malignancies, characterized by aggressive
biological behavior, profound desmoplasia, and resistance to almost all
existing therapeutic modalities. Oncolytic viruses (OVs) have emerged as a
promising class of immunotherapeutic agents capable of inducing selective tumor
cell lysis while simultaneously activating antitumor immunity. Among the
various OV platforms, engineered influenza A viruses—including strains derived
from avian influenza H5—have gained increasing attention due to their natural
tropism, genetic flexibility, and strong capacity to stimulate innate immune
pathways. This review synthesizes the historical foundations, mechanistic
insights, preclinical evidence, and translational challenges of influenza
A–based oncolytic virotherapy for pancreatic cancer. Existing studies show that
influenza A viruses can directly lyse PDAC cells (Kasloff et al., 2014)
and can be engineered to express immunomodulatory payloads, including cytokines
and immune checkpoint inhibitors (van Rikxoort et al., 2012; Lei, G. et al,
2023). Recent advances have elucidated the
role of cGAS–STING signaling and enhanced cytotoxic lymphocyte infiltration in
mediating influenza-based antitumor effects. Despite compelling preclinical
data, no influenza-derived OV has yet entered clinical trials for PDAC. Further
research is required to optimize tumor selectivity, improve delivery
strategies, and overcome stromal and immunologic barriers. This review
highlights current progress and proposes future directions to facilitate the
translation of influenza-based virotherapy into clinical applications for PDAC.
Keywords: Pancreatic ductal adenocarcinoma;
oncolytic viruses; influenza A–based virotherapy; H5 avian influenza; antitumor
immunity; cGAS–STING pathway; tumor microenvironment; immunomodulatory
payloads; preclinical oncology.
1. Introduction
Pancreatic ductal adenocarcinoma
accounts for over 90% of pancreatic cancer cases and continues to exhibit
mortality rates among the highest of all cancers, with a 5-year survival rate
remaining below 10%. Its lethality is attributed to late clinical presentation,
extensive desmoplastic stroma, profound immunosuppression, and resistance to
chemotherapy, radiotherapy, and most immunotherapies (Hamidi-Sofiani et al.,
2022; Achim et al., 2025). In response to these challenges, oncolytic viruses
have emerged as a distinctive therapeutic modality that combines direct tumor
cell lysis with robust immune activation (Lin et al., 2023).
While several OV platforms—such as
adenovirus, vesicular stomatitis virus, herpes simplex virus, and vaccinia
virus—are undergoing active clinical development, a growing body of evidence
suggests that influenza A viruses hold unique advantages. Engineered influenza
strains, including those derived from avian influenza H5N1, possess a segmented
genome that facilitates genetic manipulation, can potently activate innate
immunity, and may be redirected toward tumor tissue (van Rikxoort et al., 2012;
Donelan & NCI, 2016).
This review provides a
comprehensive narrative synthesis of the historical development, mechanistic
rationale, preclinical evidence, and translational opportunities associated
with influenza A–based oncolytic virotherapy for pancreatic cancer.
2. Methods
This narrative review was conducted
using peer-reviewed literature published between 2012 and 2025. Searches were
performed in PubMed, Scopus, and Web of Science using the terms oncolytic
influenza virus, H5N1 engineered virus, influenza virotherapy,
and pancreatic ductal adenocarcinoma. Key historical studies published
prior to 2020 were included to ensure adequate background contextualization,
while publications from 2020–2025 were prioritized to reflect contemporary
knowledge and translational developments. Only literature indexed in major
scholarly databases and publicly archived was included. All references follow
APA citation style.
3. Historical Development of
Influenza A as an Oncolytic Virus
Early observations of respiratory
viral infections demonstrated that certain viruses could induce cytopathic
effects in malignant cells. These findings laid the conceptual foundation for
exploring influenza viruses as potential oncolytic agents. The development of
reverse genetics techniques enabled precise engineering of influenza A viruses,
including the integration of immunostimulatory genes. A landmark study by van
Rikxoort et al. (2012) demonstrated that insertion of interleukin-15
(IL-15) into the NS reading frame increased antitumor immune activation,
solidifying the feasibility of arming influenza A with therapeutic payloads.
The National Cancer Institute
formally defined an “oncolytic influenza A virus” as a genetically engineered
influenza virus capable of selectively infecting and destroying cancer cells
(Donelan & NCI, 2016), recognizing its potential as a distinct OV platform.
The first major evidence of influenza A’s direct oncolytic activity against
PDAC was provided by Kasloff et al. (2014), who demonstrated infection,
replication, and tumor growth inhibition in human PDAC xenografts. This study
established the rationale for further exploring influenza-based OVs as
candidate therapeutics for pancreatic cancer.
4. Mechanisms of Action of
Influenza-Based Oncolytic Virotherapy
4.1 Selective Infection and Lysis
of Tumor Cells
Influenza A virus tropism is
largely determined by sialic acid receptor specificity. Human PDAC cells
express both α2,3- and α2,6-linked sialic acids, which facilitate efficient
viral entry (Kasloff et al., 2014). Following infection, the influenza
virus undergoes replication and induces lytic cell death, leading to reduced
tumor viability. This direct cytopathic effect represents a foundational
mechanism of influenza-based OV therapy.
4.2 Induction of Innate Immune
Responses
Influenza A viruses robustly
activate pattern-recognition receptors, including RIG-I, TLR7, and the
cGAS–STING pathway. Activation of these sensors results in the release of type
I interferons, chemokines, and inflammatory cytokines that collectively enhance
antitumor immunity (Lei, G. et al, 2023). This innate signaling may help
counteract the profoundly immunosuppressive microenvironment characteristic of
PDAC.
4.3 Activation of Adaptive
Antitumor Immunity
Engineered influenza A viruses
enhance adaptive immune responses through activation of dendritic cells,
increased antigen presentation, and expansion of cytotoxic CD8+ T lymphocytes.
Recent studies show that influenza-based OVs engineered to express PD-L1–neutralizing
antibodies enhance T-cell infiltration and reverse T-cell exhaustion (Lei, G. et
al, 2023). These findings suggest that influenza-derived OVs can potentiate
antitumor immunity through coordinated innate and adaptive mechanisms.
4.4 Delivery of Immunomodulatory
Payloads
Advances in genetic engineering
have enabled influenza A viruses to deliver biologically active therapeutic
molecules. These include IL-15 (van Rikxoort et al., 2012), anti–PD-1 or
anti–PD-L1 antibodies (Lei, G. et al., 2022), and GM-CSF (Reddy et al., 2024). Such
payloads further amplify antitumor immune responses and may synergize with
existing immunotherapies.
5. Preclinical Evidence in
Pancreatic Cancer
5.1 Direct Evidence from PDAC
Models
The study by Kasloff et al.
(2014) remains the principal direct investigation demonstrating that avian
influenza A can infect human PDAC cells, replicate efficiently, induce
apoptosis, and inhibit tumor growth in xenograft models. Although limited, this
foundational evidence confirms that PDAC is permissive to influenza-based OV
therapy.
5.2 Mechanistically Relevant
Studies in Other Solid Tumors (2020–2025)
Since influenza OVs for PDAC are
still emerging, supporting mechanistic insights derive from preclinical studies
in hepatocellular carcinoma, colorectal cancer, and other solid tumors. These
include demonstrations that influenza A viruses expressing PD-L1 antibodies
enhance CD8+ T-cell activation via cGAS–STING signaling (Lei, G. et al,
2023), and that anti–PD-1-armed influenza viruses suppress tumor progression
and extend survival (Lei, G. et al.,
2022). Collectively, these findings provide strong mechanistic support for
application in PDAC.
5.3 Relevance to the Immunobiology
of PDAC
The fibrotic and immunosuppressive
microenvironment of PDAC poses substantial barriers to effective immunotherapy.
Influenza-based OVs exhibit properties that may overcome these barriers by
inducing inflammatory remodeling (Esteves et al., 2025), promoting
immunogenic tumor cell death, and enhancing responsiveness to checkpoint
blockade therapies (Achim et al., 2025). Accordingly, although direct
PDAC studies remain limited, the mechanistic congruence is compelling.
6. Combination Strategies for
Enhanced Efficacy
6.1 Combination with Immune
Checkpoint Inhibitors
Influenza A viruses engineered to
express anti–PD-1 or anti–PD-L1 antibodies demonstrate superior antitumor
efficacy compared with monotherapy (Lei, G. et al., 2022), highlighting
the potential for integrated immunomodulation.
6.2 Combination with Cytokine
Engineering
Arming influenza A viruses with
IL-15 promotes activation of NK cells and CD8+ T cells (van Rikxoort et al.,
2012), an advantage particularly relevant for PDAC, which exhibits suppressed
NK-cell activity.
6.3 Combination with Stromal
Modulation Strategies
The dense desmoplastic stroma of
PDAC limits viral dissemination. Potential synergistic approaches include
co-administration of TGF-β inhibitors, hyaluronidase, or CXCR4 antagonists,
which may enhance viral penetration and promote microenvironmental remodeling
(Rivers-Orellana et al., 2025).
7. Challenges and Limitations
7.1 Biosafety and Risk of
Pathogenic Reversion
Because influenza viruses possess
inherent pathogenicity—particularly avian-derived strains—engineering efforts
must incorporate stringent safety features to ensure attenuation in normal
tissues and prevent reversion to virulence (Sułek et al., 2025).
7.2 Barriers to Efficient Delivery
The extracellular matrix of PDAC
restricts viral distribution, and systemic delivery is further impeded by
neutralizing antibodies and interferon responses. These barriers necessitate
innovative delivery approaches and improved viral design.
7.3 Lack of Clinical Translation
Despite encouraging preclinical
studies, no influenza-based oncolytic viruses have entered clinical trials for
PDAC. Major translational gaps include optimization of tumor specificity,
reliable biomanufacturing, and development of predictive animal models.
8. Future Directions
8.1 Development of Multi-Armed
Influenza OVs
Emerging platforms may integrate
multiple mechanisms—lysis, checkpoint inhibition, cytokine support, and stromal
remodeling—within a single viral vector to maximize efficacy.
8.2 Personalized Virotherapy Based
on Tumor Profiling
Advances in neoantigen mapping and
receptor profiling may enable individualized influenza A OV designs tailored to
specific tumor characteristics (Vorobjeva et al., 2022).
8.3 Integration with mRNA Vaccines
or Cell-Based Immunotherapies
Influenza OVs may serve as priming
agents to enhance the effectiveness of mRNA vaccines or CAR-T therapies,
particularly by reshaping the tumor microenvironment.
9. Conclusion
Oncolytic influenza A viruses
represent a highly promising yet underdeveloped therapeutic platform for
pancreatic ductal adenocarcinoma. Foundational studies demonstrate their
capacity for selective tumor cell infection and lysis, while more recent engineering
advances have enabled delivery of immunomodulatory payloads and synergy with
immune checkpoint blockade. Although substantial mechanistic evidence supports
their application in PDAC, barriers related to biosafety, delivery, and
translational validation must be addressed. Continued research into genetic
optimization, stromal penetration, and microenvironment modulation will be
essential for advancing influenza-based oncolytic virotherapy toward clinical
evaluation. With ongoing improvements in synthetic virology and
immuno-oncology, influenza A OVs hold significant potential to contribute to
future therapeutic strategies for PDAC.
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