An oncolytic vaccinia virus encoding CD47 nanobody potentiates antitumor immunity in multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy exhibiting immune evasion and resistance to proteasome inhibitors like bortezomib. We engineered an oncolytic vaccinia virus encoding an anti-mouse CD47 nanobody (OVV-αCD47nb) that combines direct oncolysis with localized CD47-SIRPα axis blockade. OVV-αCD47nb maintained infectivity and secreted anti-CD47 nanobodies that enhanced macrophage phagocytosis of tumor cells. In murine MM models, OVV-αCD47nb suppressed tumor growth, extended survival, and induced durable responses without hematologic toxicity. Mechanistically, OVV-αCD47nb remodeled the tumor microenvironment by polarizing macrophages to M1-like phenotypes and enhancing CD8+ T cell infiltration and function. Transcriptomics revealed enriched pro-inflammatory and phagocytic pathways with downregulated autophagy genes. OVV-αCD47nb synergized with bortezomib to overcome resistance and improve tumor control over monotherapies. This multifunctional viro-immunotherapy strategy, which integrates oncolysis, immune reprogramming, and chemosensitization, offers a promising therapeutic approach for CD47-expressing malignancies.