Parvoviruses are small, non-enveloped, single-stranded DNA viruses. Unlike most oncolytic platforms, several members inherently prefer rapidly proliferating tumor cells, not through genetic engineering but because their life cycle depends on mitotic host cells. Their non-structural protein 1 (NS1) is the principal effector of this natural oncolytic activity. Integrating current knowledge of its structure, tumor-killing mechanism and translational development, we argue that NS1 constitutes a distinct class of oncolytic agents: a structurally definable and engineerable cytotoxic effector whose antitumor value does not depend on viral replication. Structurally, NS1 comprises three modules acting in concert: an N-terminal HUH endonuclease domain, a central helicase/ATPase domain, and C-terminal transactivation domain. These endow NS1 with site-specific DNA endonuclease and helicase activities as well as pro-apoptotic activity, forming the molecular basis of the intrinsic oncolytic effect of the genus parvovirus. Mechanistically, the N-terminal endonuclease introduces single-strand breaks into host genomic DNA; separately, the C-terminal transactivation domain (TAD2) activates ataxia-telangiectasia mutated and Rad3-related kinase (ATR), which phosphorylates CDC25C at Ser216 and thereby inactivates the cyclin B/CDK1 complex, imposing a p53-independent G2 arrest. Because p53 is the most frequently mutated gene in the majority of human malignancies, this p53 independence is central to the broad applicability of NS1, and p53-deficient tumor cells are not less sensitive to NS1 than their wild-type counterparts. In parallel, mitochondrial damage induced by NS1 promotes sustained opening of the mitochondrial permeability transition pore (mPTP), collapse of the mitochondrial membrane potential, release of cytochrome c, an increased Bax/Bcl-2 ratio and ultimately caspase-9/3/7-dependent apoptosis. When apoptotic cells are not promptly cleared, secondary necrosis releases damage-associated molecular patterns (DAMPs) including HMGB1, extracellular ATP, HSP70 and tumor-associated antigens; notably, H-1PV infection elevates extracellular ATP release in a dose-dependent manner. These DAMPs, together with cGAS-STING activation triggered by mitochondrial DNA leakage, convert local killing into systemic immune surveillance: macrophages polarize from M2 towards an inflammatory M1 phenotype through TLR4 and P2X7 signaling and secrete TNF-α, IL-12 and IL-1β together with the chemokines CXCL9/CXCL10 that recruit natural killer (NK) cells and CD8⁺ T cells, while modulation of natural cytotoxicity receptor (NCR) ligands sensitizes NS1-expressing tumor cells to NK-mediated killing. The translational evidence forms a four-tier chain: broad cytotoxicity across human tumor cell lines; in vivo efficacy in rodent tumor models; clinical activity and safety in canine spontaneous tumors, which owing to their genetic heterogeneity and intact immune system predict human outcomes better than rodent models; and, for H-1PV, two ParvOryx trials (a phase I/IIa study in glioblastoma and a phase II study in unresectable metastatic pancreatic ductal adenocarcinoma) demonstrating a favorable safety profile with evidence of immune activation. Four interlocking bottlenecks still separate NS1 from routine clinical use: host immune clearance of delivery vectors, insufficient tumor-targeted delivery, the manufacturing paradox arising from NS1 cytotoxicity to producer cells, and tumor resistance and immune evasion. We therefore propose 3 viewpoints. First, the field is moving from oncolytic whole viruses towards a defined NS1 effector drug: non-viral delivery of NS1-encoding plasmids by lipoplexes or engineered exosomes would decouple NS1 cytotoxicity from viral replication and alleviate the constraints of immune clearance, biosafety and manufacturing. Second, companion-dog spontaneous tumor trials constitute the most leveraged translational bridge and should serve as the mandatory pre-registration platform for NS1-based agents. Third, the intrinsic immunogenicity of NS1-induced cell death makes NS1 a natural partner for immune checkpoint inhibitors, and cold-to-hot conversion of the tumor microenvironment should guide rational combination design. This integrated picture should inform the development of NS1-based oncolytic drugs over the next five to ten years.