Virus nanotechnology for intratumoural immunotherapy

Abstract

Viruses can be designed to be tools and carrier vehicles for intratumoural immunotherapy. Their nanometre-scale size and shape allow for functionalization with or encapsulation of medical cargoes and tissue-specific ligands. Importantly, immunotherapies may particularly benefit from the inherent immunomodulatory properties of viruses. For example, mammalian viruses have already been tested for oncolytic virotherapy, and bacteriophages and plant viruses can be engineered for immunotherapeutic treatment approaches. In this Review, we discuss how viruses - including oncolytic viruses, immunomodulatory plant viruses and bacteriophages - and virus-like particles can be designed for intratumoural immunotherapy to elicit anti-tumour immunity and induce systemic anti-tumour responses at distant non-injected sites. We further highlight the engineering of viruses and virus-like particles as drug-delivery systems, and outline key translational challenges and clinical opportunities.

Fig. 1 |. Cancer-immunity cycle.

Antigens are released from dead or dying cancer cells. These antigens are then presented by dendritic cells and trafficked to lymph nodes, where T cells are primed and activated. Activated T cells infiltrate tumour sites to induce more cancer-cell death. The cancer-immunity cycle can be activated by oncolytic viruses that infect cancer cells to trigger their oncolysis and subsequent antigen release. Alternatively, viruses and virus-like particles (VLPs) can be designed to bind to specific receptors on cancer cells, promoting stimulation of the immune system by stimulating type I interferon (IFN) signalling.

Fig. 2 |. Milestones of virus nanotechnology and immunotherapy.

CAR-T cell, chimeric antigen receptor T cell; CTLA-4; cytotoxic T-lymphocyte-associated antigen 4. Data are taken from refs. ,,,,,,–,,–,,,.

Fig. 3 |. Research and investment in oncolytic viruses.

a, Peer-reviewed publications in 1990–2024 involving different types of oncolytic virus. Search terms in PubMed: [oncolytic virus] AND [cancer] AND [virus type name]. b, Clinical trials using oncolytic viruses in 1990–2024. Oncolytic viruses undergoing clinical trials were extracted from the Clinicaltrials.gov database using the following keywords in titles and abstracts: oncolytic virus, adenovirus, poxvirus, vaccinia, coxsackievirus, herpes simplex virus (HSV), measles virus, Newcastle disease virus, parvovirus, reovirus, Seneca Valley virus, vesicular stomatitis virus (VSV), poliovirus and cancer. c, Patents filed for oncolytic-virus platforms from 2010 to 2024 in the USA. Search terms in Google patents include [oncolytic virus] AND [cancer] + [country = USA].

Fig. 4 |. Mechanism of action of virus-based intratumoural immunotherapy.

a, Oncolytic viruses selectively infect and lyse tumour cells to release antigens. Antigens are used by dendritic cells to prime CD8+ T cells, which induce tumour killing. b, Plant viruses and virus-like particles (VLPs) are recognized by the immune system, which, in response, launches an activation programme. Recognized antigens prime CD8+ T cells for tumour killing. TME, tumour microenvironment; TVEC, herpes simplex virus 1; PVSRIPO, poliovirus; CAVATAK, coxsackievirus.

Fig. 5 |. Structure and scale of viruses and virus-like particles used for intratumoural immunotherapy.

Virus and virus-like particle (VLP) structures are diverse. This allows them to be engineered for intratumoural immunotherapy. Mammalian viruses include the herpes simplex virus 1 (TVEC; Protein Data Bank ID (PDB): 6CGR), adenovirus (DNX-2401; PDB: 6CGV) and poliovirus (PVSRIPO; PDB: 1POV). TVEC is currently approved for melanoma, and DNX-2401 and PVSRIPO are currently being tested in clinical trials. Cowpea mosaic virus (CPMV; PDB: 1NY7), M13 bacteriophage (PDB: 2MJZ), the Alphaflexiridae plant viruses papaya mosaic virus (PapMV) and potato virus X (PVX; PDB: 4DOX), cowpea chlorotic mottle virus (CCMV; PDB: 1ZA7), Qβ bacteriophage (PDB: 1QBE) and MS2 bacteriophage (PDB: 2MS2) are currently in the preclinical development pipeline. Viruses and VLPs can deliver Toll-like receptors (TLRs) and stimulator of interferon gene (STING) agonists.

Box Fig. 1 |

a, Genetic arrangement and homology between CPMV and poliovirus. P1 is the region encoding poliovirus structural proteins (the capsid). P2 and P3 are the regions encoding poliovirus nonstructural proteins (viral genome protein, protease and RNA-dependent RNA polymerase). L-CP, S-CP, large- and small-coat proteins, respectively; MP, movement protein; NTBM, NTP binding motif; Pro, protease; ProC, protease cofactor; RdRp, RNA-dependent RNA polymerase; Vpg, viral genome protein. b, The Protein Data Bank ID (PDB) entries for coat proteins are 1NY7 (CPMV) and 1POV (polio).