In situ vaccination for the treatment of localized cancer and the prevention of metastatic disease

Abstract

In situ vaccination (ISV) is a local tumor-directed immunotherapy strategy that uses a treated tumor as an endogenous, patient-specific source of tumor antigens and a site of immune activation, with the goal of converting local treatment into systemic and durable antitumor immunity. Depending on the modality, ISV induces immunogenic cell death, other forms of tumor-cell stress or death, or local innate immune activation, thereby increasing antigen availability, promoting type I interferon signaling, and supporting dendritic cell–mediated cross-priming of tumor-reactive T cells capable of mediating both local and systemic antitumor immunity, including regression of untreated lesions. Across immunocompetent preclinical models, ISV can generate durable local tumor control, abscopal responses, and long-term immune memory, particularly when combined with modalities that amplify antigen release or inflammatory signaling. Early clinical studies employing intratumoral innate immune agonists, radiotherapy-based regimens, cytokines, and oncolytic viruses demonstrate clinical feasibility, favorable safety profiles, and emerging evidence of systemic efficacy in selected tumor types. In this review, we discuss the immunologic principles underlying ISV and organize the field according to major triggering modalities, including radiotherapy, ablation, and light-based therapies, selected chemotherapies, innate immune agonists, cytokines, and oncolytic viruses. We further highlight emerging intratumoral delivery platforms, such as lipid nanoparticles, injectable hydrogels, and biodegradable scaffolds, that enable precise spatial and temporal control of immune activation within the tumor microenvironment. Finally, we review the evidence that locally initiated antitumor immunity can extend beyond the treated lesion to control untreated lesions and metastatic disease, and discuss the challenges associated with achieving durable systemic efficacy and preventing recurrence.