Development of Oncolytic Virus-Proteolysis-Targeting Chimera Conjugates for Tumor Immunotherapy.

Engineering Nonpathogenic Bacteria for Synergistic Tumor-Targeted Protein Degradation and Immunotherapy by Checkpoint-Inhibiting Nanobodies.

In vivo administration of engineered microbes led to marked tumor growth inhibition in both subcutaneous breast and orthotopic hepatocellular carcinoma models, along with prolonged animal survival, driven by remodeling of the suppressive tumor microenvironment through coordinated crosstalk between M1-like macrophages and tumor-resident memory (TRM)-like CD8+ T cells.

Position-specific polymeric-coated oncolytic adenovirus improves anti-tumor efficacy and evades neutralizing antibodies in pancreatic cancer models.

Enhancing the safety and efficacy of systemically administered oncolytic adenoviruses remains a significant challenge to achieve effective targeting of primary tumors and disseminated disease. Intravenous administration exposes viral particles to various blood components interfering with their therapeutic activity. To protect adenoviruses from the inactivating factors we developed a shielding strategy based on a nanoparticle formulation reactive to a specific-site in the hexon hypervariable region 1. We propose a novel coating approach based on the combination of a bioresponsive oligopeptide-modified poly(β-aminoester)s (OM-PBAE-CRRR) and an irreversible linear PEG polymer with protruding ends to shield the oncolytic adenovirus AdNuPARc-E (PEPB). The formulated virus displays a slight delay in the transduction and replicative capacity at early time points that normalizes in a few days. Interestingly, similar oncolytic efficacy to the naked virus was observed in vitro, with enhanced antitumor effect in vivo in a pancreatic cancer model. In accordance, PEPB showed significantly enhanced pharmacokinetics and increased liver and tumor transduction in the xenograft model. In the presence of neutralizing antibodies (NAbs) coated viral particles maintained the infectivity and the replication capacity. Notably, in pre-immunized immunocompetent mice, protection from NAbs resulted in a higher viral accumulation in tumors than in the liver and was associated with significant antitumor activity. In summary, our findings indicate that the proposed formulation PEPB -the oncolytic adenovirus AdNuPARc-E site-specifically shielded with OM-PBAE-CRRR/PEG - offers a promising approach to improve tumor targeting after systemic administration, even in the presence of pre-existing neutralizing antibodies.

TROP2-targeting chimeras (TRTACs) for tumor-selective membrane protein degradation and enhanced drug delivery

These findings establish TROP2 as a robust LTR and provide a versatile eTPD platform with profound translational potential for tumor treatment, as well as design TRTAC-drug conjugates, enabling targeted protein degradation together with enhanced drug delivery.

Self-assembled protein-aptamer nanoparticles for targeted cancer immunotherapy.

Developing effective delivery methods for therapeutic proteins poses a major challenge in oncology. Protein drugs offer targeted mechanisms against tumor cells, minimizing off-target effects and potential for personalized therapy. Our study proposes a controllable in situ self-assembly strategy to construct FimH protein-based nanoparticles incorporating mIFP protein and PD-L1 aptamer, demonstrating potential for targeted protein delivery and tumor therapy. The PD-L1 aptamer exerts its effect by disrupting immune checkpoints, thereby modulating immune checkpoints and promoting immune cell activity, ultimately enhancing anti-tumor responses. The FimH protein plays a role in immune activation, which may promote T cell responses and further enhances in vivo tumor suppression. Furthermore, doxorubicin (DOX) induces tumor cell apoptosis, and its combination with immunotherapy results in a synergistic attack on the tumor. The self-assembled nanoparticles facilitate the efficient transport of therapeutic proteins to the tumor site, thereby mitigating renal clearance and enzymatic degradation in vivo. Additionally, the presence of mIFP enables in vivo imaging. In murine models, PD-L1 aptamer-protein nanoparticles suppressed primary colorectal tumors and inhibited distant, untreated tumors. This controlled formation of protein nanoparticles for targeted delivery offers a versatile platform for protein-based tumor therapies.

An engineered oncolytic parapoxvirus induces immunogenic tumor cell death and displays antitumor efficacy by enhancing T cell responses.

When oncolytic viruses get on CAR: a synergic approach for solid tumor immunotherapy

Chimeric antigen receptor (CAR)-based cell therapies have transformed the treatment of selected hematologic malignancies, yet their efficacy in solid tumors remains limited due to antigen heterogeneity, inadequate trafficking, physical and metabolic barriers, immune suppression, and poor persistence of transferred cells. Oncolytic viruses (OV) provide a complementary therapeutic platform because they can selectively infect and lyse tumor cells, release tumor antigens and danger signals, remodel the tumor microenvironment, and deliver immunomodulatory payloads directly into tumor tissue. Increasing evidence suggests that rational OV–CAR combinations can convert the tumor from a passive target into an active site of immune amplification. In this review, we discuss the biological rationale and emerging engineering strategies by which OVs can enhance CAR-T and CAR-NK cell therapy. We highlight mechanisms including immunogenic tumor debulking, OV-mediated delivery of synthetic or additional CAR target antigens, local expression of cytokines and chemokines, viral production of immune engagers and checkpoint modulators, and carrier-cell approaches that improve intratumoral delivery. We further use glioblastoma (GBM) as a case study to emphasize how viral antigen delivery and cytokine-armed OVs may address antigen escape, poor persistence, and the immunosuppressive brain tumor microenvironment. Finally, we outline translational challenges, including safety, antiviral immunity, dosing sequence, patient selection, and manufacturing. The next generation of OV–CAR therapy will likely require integrated design of the virus, immune effector cells, delivery route, and biomarker-guided clinical strategy.