My long-term vision is to improve the treatment of metastatic disease through clinical research. I believe this can only be achieved through challenging the prevailing view that metastases are always widespread and incurable. My laboratory utilizes integrative molecular analyses of clinical metastases, bioinformatics and computational tools, tumor models, molecular biology, immunologic analyses, and statistical modeling to investigate: (1) biological mechanisms that restrict the potential curability of patients with limited metastatic disease following localized therapies, such as surgery and ablative radiotherapy, and (2) the interplay between ablative radiotherapy and immune checkpoint blockade in patients with metastatic disease. We discovered the first biological basis for curable metastasis in patients with colorectal cancer who underwent surgical resection of limited de novo liver metastases, whereby robust adaptive immune activation in concert with favorable clinical factors was associated with a 10-year overall survival of ~95% following surgery (Nature Communications 2018). Recently, we discovered that concurrent administration of ablative radiotherapy with immunotherapy augmented local tumor immunity and improved survival in patients with highly aneuploid non-small cell lung cancer (Nature Cancer 2022). In addition, we validated a tumor aneuploidy score as a novel biomarker of immunotherapy response across multiple human cancers (Nature Genetics 2022). I anticipate these findings will ultimately have important implications in the delineation of those patients with potentially curable metastatic disease from those whose few metastases are part of a large cascade of widespread disease, thereby advancing the paradigm for the treatment of metastatic cancers.