Synergistic Viro-chemoimmunotherapy in Breast Cancer Enabled by Bioengineered Immunostimulatory Exosomes and Dual-Targeted Coxsackievirus B3

Abstract

Breast cancer's immunosuppressive environment hinders effective immunotherapy, but oncolytic viruses hold promise for addressing this challenge by targeting tumor cells and altering the microenvironment. Yet, neutralizing antibodies and immune clearance impede their clinical utility. This study explored microRNA-modified coxsackievirus B3 (miR-CVB3), an innovative oncolytic virus, and its potential in breast cancer treatment. It investigated miR-CVB3's impact on immune-related proteins and utilized exosomes as both protective shields and delivery carriers. Results demonstrated miR-CVB3's capacity to reshape immune-related protein profiles toward a more immunostimulatory state and enhance exosome-mediated immune cell activation. Notably, cancer cell-released exosomes encapsulating miR-CVB3 (ExomiR-CVB3) maintained its antitumor cytotoxicity and bolstered its immunostimulatory effects. Moreover, ExomiR-CVB3 shielded miR-CVB3 from neutralizing antibodies and rapid immune clearance when it was systemically administered. Building on these findings, ExomiR-CVB3 was engineered with the AS1411 aptamer and doxorubicin (ExomiR-CVB3/DoxApt), enhancing therapeutic efficacy. This notable approach, combining genomic modification, aptamer surface decoration, and doxorubicin addition, demonstrated safe delivery of CVB3 to cancer cells. Comprehensive in vitro and in vivo analyses revealed selective breast cancer cell targeting, cell death induction, and significant immune cell infiltration within the tumor microenvironment while sparing healthy organs. In summary, this study highlights ExomiR-CVB3/DoxApt as a pioneering breast cancer treatment strategy adaptable for diverse cancer types, offering a potent and versatile approach to reshaping cancer immunotherapy.

Emerging delivery strategy for oncolytic virotherapy

“…The final therapeutic platform ExomiR-CVB3/DoxApt demonstrated improved targeting and cytotoxic capabilities against subcutaneous breast cancer in mice after intraperitoneal injection. 72 In addition to using naturally secreted cell particles, some studies have reported the generation of artificial enveloped viruses by co-extruding OAs with cancer cell membranes. This method not only preserved the virus’s activity, but also enhanced its anti-tumor capabilities after intratumoral injection.…”

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis

“…Cancer immunotherapy has become a viable therapeutic option for the treatment of various cancers. , However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapeutic strategies . Oncolytic viruses (OVs) have gained significant attention in cancer therapy due to their strong ability to induce immunogenic cell death (ICD). , It has been shown that OVs can drive antitumor immunity and alleviate the immunosuppressive TME by releasing tumor-associated antigens (TAAs) to recruit T cells to the immune-excluded or immune-abandoned TME. − OVs have also shown promise in improving the efficacy of immune checkpoint blockade (ICB) therapies. ,− Despite the encouraging potential of OVs and the fact that various OVs are under clinical investigation, OVs monotherapy or combination with immune checkpoint inhibitors (ICIs) have not achieved satisfactory clinical results. − Therefore, exploring the mechanisms underlying the poor outcome of OVs therapy and optimizing OVs therapeutic strategies has become a top priority.…”