Reprogramming the Myeloid-T Cell Ecosystem through Engineered Oncolytic Viruses for Durable Antitumor Immunity

Oncolytic virotherapy (OVT) has emerged as a promising immunotherapeutic strategy that combines selective tumor destruction with systemic immune activation. However, durable clinical responses remain limited because current approaches largely focus on viral replication and oncolysis while overlooking the immune networks that govern long-term tumor control. Emerging evidence indicates that therapeutic efficacy is determined by the dynamic interplay between myeloid and T-cell populations, which collectively regulate antigen presentation, T-cell priming, effector function and immune suppression. In this Review, we propose the myeloid-T cell ecosystem as a conceptual framework for understanding and optimizing OVT. We discuss how engineered oncolytic viruses function as programmable immune modulators that simultaneously enhance antigen presentation, reprogram immunosuppressive myeloid cells, relieve MDSC-mediated inhibition and reinforce productive crosstalk with effector T cells. We further highlight viral engineering strategies and rational combination therapies that coordinately engage innate and adaptive immunity to reshape the tumor immune microenvironment. Finally, we discuss key challenges, including tumor heterogeneity, the balance between antiviral and antitumor immunity, viral delivery and biosafety. We argue that the future of OVT lies in precisely engineering the myeloid-T cell ecosystem to convert transient antiviral inflammation into durable, self-sustaining antitumor immunity, providing a conceptual roadmap for next-generation precision viro-immunotherapy.