Oncolytic viruses (OVs) represent a promising strategy in cancer immunotherapy, as they selectively infect and lyse tumor cells while simultaneously triggering robust antitumor immune responses. By inducing immunogenic cell death, OVs enhance tumor antigen presentation and initiate a systemic immune response, effectively transforming the tumor microenvironment from an immune-suppressive state to an immune-permissive state. In addition to exerting direct oncolytic effects, OVs modulate key tumor-associated biological processes, including tumor angiogenesis and extracellular matrix remodeling, disrupting tumor progression and metastasis. Notably, recent advances have highlighted the therapeutic potential of combining OVs with conventional and emerging cancer treatments, such as chemotherapy, radiotherapy, immune checkpoint inhibitors, adoptive cell therapy, and epigenetic-targeted drugs. These combination strategies demonstrate synergistic effects by improving tumor selectivity, increasing antitumor immunity, and overcoming treatment resistance. Nevertheless, persistent challenges, such as viral dissemination dynamics, therapy resistance, and regulatory complexities, impede the broad clinical implementation of oncolytic virus therapy (OVT). In this Review, we illustrate recent advancements and innovative therapeutic strategies in OVT within the context of contemporary cancer treatment paradigms. First, we outline the historical evolution and key milestones in OVT development. We then discuss the classification of OVs and their multimodal mechanisms that target tumorigenesis, metastasis, disease recurrence, and therapy resistance. Finally, we evaluate the clinical research progress of OVT applications, focusing on their integration with other therapies, analyze the translational barriers hindering clinical implementation, and propose evidence-based future directions for optimizing cancer treatment.

Lectins are widely existed in marine bioresources, and some purified marine lectins were found toxic to cancer cells. In this report, genes encoding Dicentrarchus labrax fucose-binding lectin (DlFBL) and Strongylocentrotus purpuratus rhamnose-binding lectin (SpRBL) were inserted into an adenovirus vector to form Ad.FLAG-DlFBL and Ad.FLAG-SpRBL, which elicited significant in vitro suppressive effect on a variety of cancer cells. Anti-apoptosis factors Bcl-2 and XIAP were determined to be downregulated by Ad.FLAG-DlFBL and Ad.FLAG-SpRBL. Subcellular localization studies showed that DlFBL but not SpRBL widely distributed in membrane systems. Both DlFBL and SpRBL were shown associated with protein arginine methyltransferase 5 (PRMT5), and PRMT5-E2F-1 pathway was suggested to be responsible for the DlFBL and SpRBL induced apoptosis. Further investigations revealed that PRMT5 acted as a common binding target for various exogenous lectin and non-lectin proteins, suggesting a role of PRMT5 as a barrier for foreign gene invasion. The cellular response to exogenous lectins may provide insights into a novel way for cancer gene therapy.

Lectins display a variety of biological functions including insecticidal, antimicrobial, as well as antitumor activities. In this report, a gene encoding Aphrocallistes vastus lectin (AVL), a C-type lectin, was inserted into an oncolytic vaccinia virus vector (oncoVV) to form a recombinant virus oncoVV-AVL, which showed significant in vitro antiproliferative activity in a variety of cancer cell lines. Further investigations revealed that oncoVV-AVL replicated faster than oncoVV significantly in cancer cells. Intracellular signaling elements including NF-κB2, NIK, as well as ERK were determined to be altered by oncoVV-AVL. Virus replication upregulated by AVL was completely dependent on ERK activity. Furthermore, in vivo studies showed that oncoVV-AVL elicited significant antitumor effect in colorectal cancer and liver cancer mouse models. Our study might provide insights into a novel way of the utilization of marine lectin AVL in oncolytic viral therapies.

Lectins exist widely in marine bioresources such as bacteria, algae, invertebrate animals and fishes. Some purified marine lectins have been found to elicit cytotoxicity to cancer cells. However, there are few reports describing the cytotoxic effect of marine lectins on cancer cells through virus-mediated gene delivery. We show here that a replication-deficient adenovirus-carrying gene encoding Haliotis discus discus sialic acid binding lectin (Ad.FLAG-HddSBL) suppressed cancer cell proliferation by inducing apoptosis, as compared to the control virus Ad.FLAG. A down-regulated level of anti-apoptosis factor Bcl-2 was suggested to be responsible for the apoptosis induced by Ad.FLAG-HddSBL infection. Further subcellular localization studies revealed that HddSBL distributed in cell membrane, ER, and the nucleus, but not in mitochondria and Golgi apparatus. In contrast, a previously reported mannose-binding lectin Pinellia pedatisecta agglutinin entered the nucleus as well, but did not distribute in inner membrane systems, suggesting differed intracellular sialylation and mannosylation, which may provide different targets for lectin binding. Further cancer-specific controlling of HddSBL expression and animal studies may help to provide insights into a novel way of anti-cancer marine lectin gene therapy. Lectins may provide a reservoir of anti-cancer genes.

Oncolytic vaccinia virus has been developed as a novel cancer therapeutic drug in recent years. Our previous studies demonstrated that the antitumor effect of oncolytic vaccina virus harboring Aphrocallistes vastus lectin (oncoVV-AVL) was significantly enhanced in several cancer cells. In the present study, we investigated the underlying mechanisms of AVL that affect virus replication and promote the antitumor efficacy of oncolytic virus in hepatocellular carcinoma (HCC). Our results showed that oncoVV-AVL markedly exhibited antitumor effects in both hepatocellular carcinoma cell lines and a xenograft mouse model. Further investigation illustrated that oncoVV-AVL could activate tumor immunity by upregulating the expression of type I interferons and enhance virus replication by inhibiting ISRE mediated viral defense response. In addition, we inferred that AVL promoted the ability of virus replication by regulating the PI3K/Akt, MAPK/ERK, and Hippo/MST pathways through cross-talk Raf-1, as well as metabolism-related pathways. These findings provide a novel perspective for the exploitation of marine lectins in oncolytic therapy.

Lectins play diverse roles in physiological processes as biological recognition molecules. In this report, a gene encoding Tachypleus tridentatus Lectin (TTL) was inserted into an oncolytic vaccinia virus (oncoVV) vector to form oncoVV-TTL, which showed significant antitumor activity in a hepatocellular carcinoma mouse model. Furthermore, TTL enhanced oncoVV replication through suppressing antiviral factors expression such as interferon-inducible protein 16 (IFI16), mitochondrial antiviral signaling protein (MAVS) and interferon-beta (IFN-β). Further investigations revealed that oncoVV-TTL replication was highly dependent on ERK activity. This study might provide insights into a novel way of the utilization of TTL in oncolytic viral therapies.