BLT Regent Supports Oncolytic Virus Cancer Immunotherapy Research: Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy

Systemic injectable oncolytic virus therapy has achieved new progress in pyroptosis-enhanced cancer treatment.

Professor Tingbo Liang from the First Affiliated Hospital, Zhejiang University School of Medicine, Professor Pingyuan from the College of Pharmaceutical Sciences, Zhejiang University, and Professor Yuxuan Chen, in collaboration with Professor Wei Wei’s team from the Institute of Process Engineering, Chinese Academy of Sciences, and other research groups, published their findings in “ Nature Cancer” (IF = 28.5, top medical journal).

This study provides a new therapeutic paradigm for systemic oncolytic virus delivery in solid tumors through an ultrasound-activatable pyroptosis-inducing oncolytic adenovirus platform, overcoming limitations in immune clearance, tumor targeting, and insufficient antitumor efficacy.

Oncolytic virus therapy for solid tumors such as pancreatic cancer faces major challenges, including rapid clearance by pre-existing neutralizing antibodies after systemic administration, poor intratumoral bioavailability, and limited efficacy against deep and metastatic tumors. In addition, tumor heterogeneity results in incomplete viral infection and suboptimal therapeutic responses. To address these challenges, the researchers developed an immunoengineered nanovesicle-encapsulated ultrasound-controllable pyroptosis-amplifying oncolytic adenovirus platform (iNV-GOV). Through three synergistic mechanisms—immune camouflage to evade clearance, CAR-mediated tumor targeting, and ultrasound-triggered pyroptosis amplification—the platform protects oncolytic viruses from host humoral and cellular immune recognition, enables efficient tumor-specific delivery, and uses localized ultrasound-induced mild hyperthermia to activate tumor cell pyroptosis. This process accelerates intratumoral viral amplification, induces potent immunogenic cell death, reshapes the immunosuppressive tumor microenvironment, and achieves synergistic therapeutic effects when combined with PD-1 immune checkpoint inhibitors or gemcitabine chemotherapy, providing a new strategy for systemic oncolytic virus therapy in solid tumors.

The study demonstrated that the iNV-GOV platform, based on genetically engineered low-immunogenic nanovesicle-coated oncolytic viruses, effectively escaped uptake by mononuclear macrophages and immune clearance by T/NK cells. Compared with conventional vesicle-coated viruses, the in vivo circulation half-life was extended by 2.7-fold. In HER2-positive pancreatic cancer models, tumor uptake reached 37.8%, significantly higher than the 4.9% observed with unmodified vesicles, while viral accumulation was predominantly restricted to tumor tissues with minimal distribution in normal organs. Meanwhile, the heat shock promoter-regulated GSDMD-N terminal fragment was precisely activated by ultrasound to induce tumor cell pyroptosis, increasing intratumoral viral levels by 13.7-fold compared with conventional oncolytic viruses. The resulting release of damage-associated molecular patterns, including ATP, HMGB1, and calreticulin, induced stronger immunogenic cell death than oxaliplatin and irinotecan. Following treatment, the platform significantly improved the tumor-associated macrophage M1/M2 ratio, reduced regulatory T cell infiltration, promoted dendritic cell maturation, and enhanced CD8⁺ T cell recruitment, effectively converting immunologically “cold tumors” into “hot tumors” and remodeling the dense stromal and immunosuppressive microenvironment of pancreatic cancer. In vivo studies showed that iNV-GOV monotherapy significantly inhibited tumor growth in humanized orthotopic pancreatic cancer PDX models. Combination therapy with anti-PD-1 antibodies extended mouse survival beyond 80 days, while combination with gemcitabine achieved 100% long-term survival in chemotherapy-resistant pancreatic cancer models. The platform also demonstrated significant antitumor activity in liver cancer and cholangiocarcinoma PDX models. Furthermore, iNV-GOV exhibited excellent biocompatibility, consistent batch-to-batch production, compatibility with multiple viral vectors including adenovirus, AAV, and HSV-1, and no significant pathological damage to major organs or liver and kidney function. With a planned closed-scale manufacturing process, this platform shows strong clinical translation potential and provides a safe and effective oncolytic immunotherapy strategy for refractory solid tumors such as pancreatic cancer.

Experiments using BLT Regent

In the study, the research team evaluated the therapeutic effects of iNV-GOV alone and in combination with anti-PD-1 immune checkpoint inhibitors or gemcitabine chemotherapy. Guangzhou Biolight Biotechnology’ s enhanced ATP detection kit was used to measure ATP levels and other indicators to evaluate pyroptosis activation and tumor progression. The results showed that compared with saline treatment, ultrasound alone or conventional oncolytic virus therapy produced limited therapeutic effects, whereas iNV-GOV combined with ultrasound significantly suppressed tumor growth. Notably, both iNV-GOV combined with anti-PD-1 antibodies and iNV-GOV combined with gemcitabine demonstrated synergistic therapeutic enhancement. Endpoint analysis confirmed that, compared with monotherapy, combination treatments significantly reduced tumor burden and stromal fibrosis while substantially prolonging mouse survival.

DOI: org/10.1038/s43018-025-01078-y