Oncolytic Viruses: A Paradigm Shift in Cancer Treatment

Cancer remains a major global health challenge and a leading cause of morbidity and mortality. Its complex biology, intrinsic heterogeneity, and frequent resistance to conventional therapies have driven the pursuit of innovative and more effective treatment strategies. Oncolytic virus (OV) therapy has emerged as a transformative approach uniquely capable of selectively infecting and lysing tumor cells without affecting normal cells. Beyond direct oncolysis, OV modulates the tumor microenvironment (TME) and activates antitumor immune responses, providing a dual mechanism of action that distinguishes them from conventional therapies. Despite these advantages, OV monotherapy is constrained by challenges including limited tumor penetration, anti-viral immune clearance, and inter-patient variability, which can compromise therapeutic outcomes. Emerging evidence demonstrates that integrating OVs with complementary modalities such as chemotherapy, radiotherapy, targeted therapies, and many others can overcome these limitations by producing synergistic antitumor effects and enhanced immune activation. This chapter examines the ability of OVs to induce localized tumor inflammation, thereby priming the host immune system to recognize and eradicate malignant cells more effectively. We provide a comprehensive analysis of the OV mechanism of action, therapeutic potential, combination therapy strategies, translational progress, associated challenges, and future directions. By synthesizing emerging insights, this chapter underscores the paradigm-shifting potential of OVs in modern oncology and emphasizes their capacity to redefine the next generation of innovative cancer therapies.