Engineered vaccinia virus GC001 shows potent tumour killing and clean safety profile

An engineered oncolytic vaccinia virus that combines direct tumour lysis with a built-in gene-silencing payload has emerged as one of the more intriguing candidates in the next wave of cancer virotherapy. In a study published in the British Journal of Cancer, a team led by Gongchu Li of Zhejiang Sci-Tech University, working with colleagues at Hangzhou Gongchu Biotechnology, the National Institutes for Drug Control in Beijing and Southern Medical University, describes the preclinical efficacy and safety profile of GC001, a thymidine kinase-deleted oncolytic vaccinia virus engineered to express a short hairpin RNA targeting striatin-interacting protein 1, or STRIP1. The work arrives with considerable regulatory momentum behind it: in 2023, China’s National Medical Products Administration approved GC001 to enter a phase I clinical trial, making it one of a small number of armed oncolytic poxviruses to reach the clinic.

Oncolytic viruses occupy a distinctive niche in cancer therapy. Unlike cytotoxic drugs or checkpoint inhibitors, they are replicating agents: they infect tumour cells, hijack their biosynthetic machinery, produce progeny virions and lyse the host cell, releasing new infectious particles that spread to neighbouring malignant cells. Vaccinia virus has long been favoured as a backbone for this approach because it replicates efficiently in the cytoplasm, carries a large genome that tolerates the insertion of therapeutic transgenes, and has an extensive clinical history through smallpox vaccination. The deletion of the thymidine kinase gene is a well-established tumour-selectivity strategy. Because rapidly dividing cancer cells often overproduce the nucleotide substrates that compensate for this metabolic deficit, the engineered virus can complete its replication cycle preferentially inside tumours while replicating poorly, if at all, in normal tissue.

What sets GC001 apart is the second layer of engineering layered onto this backbone. The virus carries an shRNA cassette that suppresses expression of STRIP1, a core component of the STRIPAK complex, a large scaffolding assembly that integrates phosphatases and kinases within the Hippo signalling pathway. The Hippo pathway is a central regulator of organ size, cell proliferation and apoptosis, and its dysregulation has been implicated in tumour progression, metastasis and resistance to cell death across many cancer types. STRIPAK complexes have also been shown to influence how cancer cells migrate and metastasise, which made STRIP1 an attractive target for viral payload design. By delivering a gene-silencing construct directly into infected tumour cells, GC001 aims to strike the tumour with two synchronised blows: the destructive force of viral replication and a molecular disruption of a survival pathway that tumours rely upon.

The preclinical evidence for this strategy is broad. In mouse xenograft models spanning multiple cancer types, including colorectal, pancreatic and gastric cancer, GC001 demonstrated potent and broad-spectrum anti-tumour activity. Colorectal cancer cells showed suppressed growth both in tissue culture and in implanted tumours, and parallel experiments in pancreatic and gastric cancer models confirmed that the effect was not confined to a single tumour lineage. This spectrum matters clinically, because an oncolytic virus that requires a tumour-specific genetic vulnerability present in only a fraction of patients will struggle in late-stage trials. The breadth observed here suggests that the combined mechanism of viral lysis and STRIP1 knockdown operates through pathways that are active across common gastrointestinal malignancies and likely beyond.

Perhaps the most revealing part of the study is mechanistic. The researchers found that GC001 drives a sharp accumulation of reactive oxygen species, or ROS, within infected tumour cells. ROS are chemically reactive oxygen-containing molecules that, at low levels, function as signalling intermediates, but at high levels cause oxidative damage to proteins, lipids and DNA, pushing cells toward death. Critically, the team discovered that neither component alone produced this effect: STRIP1 knockdown by itself did not induce ROS accumulation, and the discussion of the data indicates that the burst of oxidative stress arises from the combinatorial activity of STRIP1 suppression and the oncolytic vaccinia backbone. The ROS surge was traced to two converging sources: degradation of NRF2, the master transcription factor that tumour cells use to mount antioxidant defences, and a reprogramming of mitochondrial metabolism that alters how the infected cell generates energy and handles electron flow.

This dual mechanism has consequences that extend beyond simple tumour cell killing. The NRF2 axis is one of the most commonly exploited antioxidant programmes in cancer, allowing malignant cells to survive the elevated basal oxidative stress that comes with rapid proliferation and metabolic rewiring. By degrading NRF2, GC001 effectively removes the tumour cell’s antioxidant shield at precisely the moment viral replication is placing it under maximal metabolic strain. The mitochondrial metabolic reprogramming component compounds this vulnerability, forcing the cell’s energy-generating organelles into a state that favours ROS production. The authors frame this as a ROS-Hippo pathway interaction: viral replication and cytotoxicity are potentiated through ROS-dependent modulation of Hippo signalling, the very pathway that STRIP1 knockdown targets directly.

The oxidative stress also appears to serve an immunological function. In both immunocompetent mouse models and humanised mouse models, GC001 stimulated measurable anti-tumour immune responses. This matters because the ultimate success of oncolytic virotherapy is generally believed to depend less on the direct killing of infected cells and more on the conversion of an immunologically cold tumour into an inflamed one. Viral infection releases tumour antigens and danger signals that recruit and activate immune cells, and the resulting response can, in principle, attack tumour cells far beyond the reach of the injected virus. The finding that GC001’s ROS-generating mechanism contributes to these immune responses adds a mechanistic bridge between the virus’s intracellular biochemistry and the systemic anti-tumour immunity observed in the animal models.

Safety, the perennial concern for any replicating virus intended for systemic or intratumoural administration, was addressed directly. In a nonhuman primate study, GC001 did not elicit significant toxicity and was well tolerated. The primate experiments were conducted under the regulatory requirements of the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the National Center for Safety Evaluation of Drugs, and co-author Xin Wang of the National Institutes for Drug Control oversaw the design and performance of these safety studies. Given that vaccinia virus retains its capacity to infect human cells, demonstrating a clean tolerance profile in a species phylogenetically close to humans is a meaningful de-risking step before the phase I trial that the NMPA authorised in 2023.

The study also sits within a rapidly maturing field. Oncolytic viruses have moved from experimental curiosity to approved medicine with talimogene laherparepvec, a modified herpes virus for melanoma, and intratumoral oncolytic herpes virus G47∆ has shown phase 2 efficacy against residual or recurrent glioblastoma. Vaccinia-based platforms have been tested intravenously in humans and are being armed with payloads ranging from interleukin-12 to anti-CTLA-4 antibodies and immune-modulating lectins. Recent work from the same group has explored oncolytic vaccinia viruses expressing CLEC2A and avian lectins that boost viral replication and ROS-mediated killing in pancreatic and gastric cancers. GC001 extends this logic into gene-silencing territory, coupling the viral platform to RNA interference aimed at a specific signalling node rather than an immune-stimulatory cytokine.

There are, of course, familiar caveats. The efficacy data derive from xenografts and mouse models, systems that have historically overpredicted clinical responses in oncology, and the funding of the study by Hangzhou Gongchu Biotechnology, together with the corresponding patent position held by the company and a founder-authored manuscript, warrants the standard attention to conflicts of interest that accompanies commercial virotherapy development. The delivery route, dosing schedule and interaction with existing immunotherapies in humans remain to be established. Even so, the combination of broad preclinical activity, a mechanistically coherent dual-action design, immune activation in immunocompetent models and a favourable tolerability profile in nonhuman primates positions GC001 as a serious clinical contender. As the phase I trial proceeds, the central question will be whether the elegant ROS-Hippo synergy observed in the laboratory survives translation into patients, and whether an armed poxvirus that silences a Hippo pathway scaffold can deliver on the promise that two decades of oncolytic virus engineering has been building toward.

Subject of Research: Oncolytic vaccinia virus therapy engineered to knock down STRIP1 for cancer treatment

Article Title: Efficacy and safety of GC001: an oncolytic vaccinia virus expressing STRIP1 shRNA

Article References: Li, G., Jiang, G., Pang, W., Cai, Z., Liu, R., Zhang, H., Zhu, J., Su, J., Zhu, B., Yu, J., Feng, H., Zhu, Y., Zhang, G., Xu, W., Ye, T., Chen, K., Zhou, Y., Pan, D., Sun, L., … Ning, Y. (2026). Efficacy and safety of GC001: an oncolytic vaccinia virus expressing STRIP1 shRNA. British Journal of Cancer. https://doi.org/10.1038/s41416-026-03618-4

Image Credits: AI Generated

DOI: 10.1038/s41416-026-03618-4

Keywords: oncolytic virus, vaccinia virus, GC001, STRIP1, Hippo pathway, reactive oxygen species, NRF2, cancer immunotherapy, virotherapy, phase I trial, colorectal cancer, mitochondrial metabolism