Facts and hopes in radioimmunotherapy of oligometastatic disease.

Abstract

The oligometastatic state, characterized by limited metastatic dissemination, challenges the view that metastatic cancer is widespread and incurable. Evidence suggests that select patients with restricted metastases may achieve long-term disease control or even cure with local therapies, such as surgery or stereotactic body radiation therapy (SBRT). Radiotherapy induces complex, dose-dependent effects on the tumor microenvironment, including the release of immunogenic cytokines and damage-associated molecular patterns (DAMPs), enhanced antigen presentation on cancer cells, and infiltration of effector T cells, natural killer (NK) cells, and macrophages. These immunomodulatory effects provide a compelling basis for combining SBRT with immune checkpoint inhibitors (ICIs) to enhance local and systemic anti-tumor immunity. Several prospective phase I-II trials have investigated various combinations of radiotherapy and immunotherapy in the oligometastatic setting, demonstrating acceptable safety profiles and promising efficacy signals. However, clinical outcomes reported with combined radioimmunotherapy have largely been mixed, which likely reflects variability in SBRT dosing, sequencing of therapy, type of immunotherapy, patient selection, and tumor characteristics. Notably, studies employing comprehensive ablative SBRT to all metastatic sites appear to more consistently demonstrate superior outcomes over standard-of-care systemic therapy, as opposed to sub-ablative or single-lesion irradiation. Advancing the therapeutic paradigm of radioimmunotherapy combinations for oligometastatic disease requires improved patient selection based on clinical, molecular, or radiographic features; rigorous optimization of radiotherapy dose-fractionation to maximize immune priming while minimizing toxicities; and rational integration with novel immunotherapeutic agents that target complementary immune pathways.